CN103209684A - Aqueous drug delivery system comprising off - flavor masking agent - Google Patents
Aqueous drug delivery system comprising off - flavor masking agent Download PDFInfo
- Publication number
- CN103209684A CN103209684A CN2011800546354A CN201180054635A CN103209684A CN 103209684 A CN103209684 A CN 103209684A CN 2011800546354 A CN2011800546354 A CN 2011800546354A CN 201180054635 A CN201180054635 A CN 201180054635A CN 103209684 A CN103209684 A CN 103209684A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- therapeutic agent
- water stability
- water
- cyclodextrin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003795 chemical substances by application Substances 0.000 title claims abstract description 91
- 239000000796 flavoring agent Substances 0.000 title claims description 83
- 235000019634 flavors Nutrition 0.000 title claims description 82
- 238000012377 drug delivery Methods 0.000 title description 8
- 230000000873 masking effect Effects 0.000 title description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 277
- 239000003814 drug Substances 0.000 claims abstract description 274
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 143
- 239000007788 liquid Substances 0.000 claims abstract description 110
- 238000000034 method Methods 0.000 claims abstract description 66
- 235000013361 beverage Nutrition 0.000 claims abstract description 53
- 239000000203 mixture Substances 0.000 claims description 196
- 229940124597 therapeutic agent Drugs 0.000 claims description 190
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical group CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 81
- 229920000858 Cyclodextrin Polymers 0.000 claims description 77
- 230000002159 abnormal effect Effects 0.000 claims description 69
- 238000002360 preparation method Methods 0.000 claims description 68
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 68
- 229940126701 oral medication Drugs 0.000 claims description 63
- 238000012216 screening Methods 0.000 claims description 58
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 56
- 239000000758 substrate Substances 0.000 claims description 46
- 229920002148 Gellan gum Polymers 0.000 claims description 44
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 39
- 229960001680 ibuprofen Drugs 0.000 claims description 31
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 30
- 229920001542 oligosaccharide Polymers 0.000 claims description 29
- 150000002482 oligosaccharides Chemical class 0.000 claims description 29
- 229960005489 paracetamol Drugs 0.000 claims description 29
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 27
- 239000011707 mineral Substances 0.000 claims description 27
- 238000012360 testing method Methods 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 23
- 229960003940 naproxen sodium Drugs 0.000 claims description 22
- CDBRNDSHEYLDJV-FVGYRXGTSA-M naproxen sodium Chemical compound [Na+].C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CDBRNDSHEYLDJV-FVGYRXGTSA-M 0.000 claims description 21
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 17
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 17
- 239000000463 material Substances 0.000 claims description 16
- 239000002243 precursor Substances 0.000 claims description 16
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims description 15
- -1 hydroxypropyl Chemical group 0.000 claims description 13
- 241001597008 Nomeidae Species 0.000 claims description 12
- 235000016709 nutrition Nutrition 0.000 claims description 12
- 241000047703 Nonion Species 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 229960004853 betadex Drugs 0.000 claims description 9
- 150000004676 glycans Chemical class 0.000 claims description 9
- 229920001282 polysaccharide Polymers 0.000 claims description 9
- 239000005017 polysaccharide Substances 0.000 claims description 9
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 8
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 5
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 5
- 229940079593 drug Drugs 0.000 abstract description 19
- 239000002775 capsule Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000008203 oral pharmaceutical composition Substances 0.000 abstract 1
- 239000011049 pearl Substances 0.000 description 62
- 150000001875 compounds Chemical class 0.000 description 51
- 229920002877 acrylic styrene acrylonitrile Polymers 0.000 description 49
- 239000000499 gel Substances 0.000 description 41
- 239000003981 vehicle Substances 0.000 description 35
- 238000004128 high performance liquid chromatography Methods 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000002609 medium Substances 0.000 description 27
- 230000035945 sensitivity Effects 0.000 description 27
- 239000002552 dosage form Substances 0.000 description 26
- 235000010755 mineral Nutrition 0.000 description 25
- 230000003213 activating effect Effects 0.000 description 24
- 230000000694 effects Effects 0.000 description 24
- 235000013599 spices Nutrition 0.000 description 24
- 238000011282 treatment Methods 0.000 description 23
- 239000007787 solid Substances 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 239000000126 substance Substances 0.000 description 18
- 235000019640 taste Nutrition 0.000 description 18
- 238000012545 processing Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 16
- 238000003860 storage Methods 0.000 description 16
- 239000004567 concrete Substances 0.000 description 15
- 230000003628 erosive effect Effects 0.000 description 15
- 235000013305 food Nutrition 0.000 description 15
- 239000011159 matrix material Substances 0.000 description 15
- 238000004458 analytical method Methods 0.000 description 14
- 239000003826 tablet Substances 0.000 description 14
- 240000007594 Oryza sativa Species 0.000 description 13
- 235000007164 Oryza sativa Nutrition 0.000 description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 13
- 239000012153 distilled water Substances 0.000 description 13
- 229940002612 prodrug Drugs 0.000 description 13
- 239000000651 prodrug Substances 0.000 description 13
- 235000009566 rice Nutrition 0.000 description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 12
- 238000000354 decomposition reaction Methods 0.000 description 12
- 230000000670 limiting effect Effects 0.000 description 12
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 12
- 235000019658 bitter taste Nutrition 0.000 description 11
- 235000014121 butter Nutrition 0.000 description 11
- 239000012530 fluid Substances 0.000 description 11
- 238000004062 sedimentation Methods 0.000 description 11
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 230000036571 hydration Effects 0.000 description 10
- 238000006703 hydration reaction Methods 0.000 description 10
- 230000001953 sensory effect Effects 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 9
- 235000009508 confectionery Nutrition 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 238000011156 evaluation Methods 0.000 description 9
- 230000000704 physical effect Effects 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 210000000582 semen Anatomy 0.000 description 9
- 239000003765 sweetening agent Substances 0.000 description 9
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 8
- 241001672694 Citrus reticulata Species 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 235000010443 alginic acid Nutrition 0.000 description 8
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 8
- 235000013736 caramel Nutrition 0.000 description 8
- 238000000576 coating method Methods 0.000 description 8
- 235000005911 diet Nutrition 0.000 description 8
- 235000003599 food sweetener Nutrition 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- 239000004615 ingredient Substances 0.000 description 8
- 239000008297 liquid dosage form Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 229940088594 vitamin Drugs 0.000 description 8
- 229930003231 vitamin Natural products 0.000 description 8
- 239000011782 vitamin Substances 0.000 description 8
- 235000014101 wine Nutrition 0.000 description 8
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 7
- 241000196324 Embryophyta Species 0.000 description 7
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical group CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 7
- 244000269722 Thea sinensis Species 0.000 description 7
- 229940072056 alginate Drugs 0.000 description 7
- 229920000615 alginic acid Polymers 0.000 description 7
- 235000013405 beer Nutrition 0.000 description 7
- 150000001720 carbohydrates Chemical class 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 239000011248 coating agent Substances 0.000 description 7
- 230000000378 dietary effect Effects 0.000 description 7
- 235000015872 dietary supplement Nutrition 0.000 description 7
- 235000013399 edible fruits Nutrition 0.000 description 7
- 238000011049 filling Methods 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 239000004571 lime Substances 0.000 description 7
- 238000009928 pasteurization Methods 0.000 description 7
- 239000002304 perfume Substances 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 235000013343 vitamin Nutrition 0.000 description 7
- 150000003722 vitamin derivatives Chemical class 0.000 description 7
- 244000228088 Cola acuminata Species 0.000 description 6
- 241001093152 Mangifera Species 0.000 description 6
- 244000299461 Theobroma cacao Species 0.000 description 6
- 230000001133 acceleration Effects 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 239000008122 artificial sweetener Substances 0.000 description 6
- 235000021311 artificial sweeteners Nutrition 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 235000014633 carbohydrates Nutrition 0.000 description 6
- 239000002131 composite material Substances 0.000 description 6
- 239000006071 cream Substances 0.000 description 6
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 6
- 239000003925 fat Substances 0.000 description 6
- 235000019197 fats Nutrition 0.000 description 6
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 6
- 229940015872 ibandronate Drugs 0.000 description 6
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 239000006187 pill Substances 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 229960004889 salicylic acid Drugs 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 235000013616 tea Nutrition 0.000 description 6
- 244000099147 Ananas comosus Species 0.000 description 5
- 235000007119 Ananas comosus Nutrition 0.000 description 5
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 5
- 241000207199 Citrus Species 0.000 description 5
- 235000016795 Cola Nutrition 0.000 description 5
- 244000241257 Cucumis melo Species 0.000 description 5
- 235000009847 Cucumis melo var cantalupensis Nutrition 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 208000002193 Pain Diseases 0.000 description 5
- 102000057297 Pepsin A Human genes 0.000 description 5
- 108090000284 Pepsin A Proteins 0.000 description 5
- 244000078534 Vaccinium myrtillus Species 0.000 description 5
- 235000009499 Vanilla fragrans Nutrition 0.000 description 5
- 244000263375 Vanilla tahitensis Species 0.000 description 5
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 5
- 230000002421 anti-septic effect Effects 0.000 description 5
- 239000011324 bead Substances 0.000 description 5
- 235000021028 berry Nutrition 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 229960001803 cetirizine Drugs 0.000 description 5
- 235000020971 citrus fruits Nutrition 0.000 description 5
- 230000029087 digestion Effects 0.000 description 5
- 235000015203 fruit juice Nutrition 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- BFBPISPWJZMWJN-UHFFFAOYSA-N methyl 2-[(7-hydroxy-3,7-dimethyloctylidene)amino]benzoate Chemical compound COC(=O)C1=CC=CC=C1N=CCC(C)CCCC(C)(C)O BFBPISPWJZMWJN-UHFFFAOYSA-N 0.000 description 5
- 235000013336 milk Nutrition 0.000 description 5
- 239000008267 milk Substances 0.000 description 5
- 210000004080 milk Anatomy 0.000 description 5
- 239000006186 oral dosage form Substances 0.000 description 5
- 229940111202 pepsin Drugs 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- 241000234282 Allium Species 0.000 description 4
- 235000002732 Allium cepa var. cepa Nutrition 0.000 description 4
- 244000144725 Amygdalus communis Species 0.000 description 4
- 235000011437 Amygdalus communis Nutrition 0.000 description 4
- 108010011485 Aspartame Proteins 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 244000089742 Citrus aurantifolia Species 0.000 description 4
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 4
- 235000005979 Citrus limon Nutrition 0.000 description 4
- 244000131522 Citrus pyriformis Species 0.000 description 4
- 235000005956 Cosmos caudatus Nutrition 0.000 description 4
- 244000293323 Cosmos caudatus Species 0.000 description 4
- 239000001116 FEMA 4028 Substances 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 4
- 102000008192 Lactoglobulins Human genes 0.000 description 4
- 108010060630 Lactoglobulins Proteins 0.000 description 4
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- 241001290151 Prunus avium subsp. avium Species 0.000 description 4
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 4
- 235000020224 almond Nutrition 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 230000003078 antioxidant effect Effects 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 239000000605 aspartame Substances 0.000 description 4
- 235000010357 aspartame Nutrition 0.000 description 4
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 4
- 229960003438 aspartame Drugs 0.000 description 4
- 235000015278 beef Nutrition 0.000 description 4
- 229960001948 caffeine Drugs 0.000 description 4
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 4
- 235000019993 champagne Nutrition 0.000 description 4
- 235000019693 cherries Nutrition 0.000 description 4
- 235000019219 chocolate Nutrition 0.000 description 4
- 235000019504 cigarettes Nutrition 0.000 description 4
- 235000013353 coffee beverage Nutrition 0.000 description 4
- 235000015142 cultured sour cream Nutrition 0.000 description 4
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000000975 dye Substances 0.000 description 4
- 239000008369 fruit flavor Substances 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 238000001879 gelation Methods 0.000 description 4
- 235000010492 gellan gum Nutrition 0.000 description 4
- 239000000216 gellan gum Substances 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- 238000005342 ion exchange Methods 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 239000002105 nanoparticle Substances 0.000 description 4
- 229960002009 naproxen Drugs 0.000 description 4
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 239000001814 pectin Substances 0.000 description 4
- 229920001277 pectin Polymers 0.000 description 4
- 235000010987 pectin Nutrition 0.000 description 4
- 235000013550 pizza Nutrition 0.000 description 4
- 235000015277 pork Nutrition 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 229960003975 potassium Drugs 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 235000013580 sausages Nutrition 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- 229920001285 xanthan gum Polymers 0.000 description 4
- NUFKRGBSZPCGQB-FLBSXDLDSA-N (3s)-3-amino-4-oxo-4-[[(2r)-1-oxo-1-[(2,2,4,4-tetramethylthietan-3-yl)amino]propan-2-yl]amino]butanoic acid;pentahydrate Chemical compound O.O.O.O.O.OC(=O)C[C@H](N)C(=O)N[C@H](C)C(=O)NC1C(C)(C)SC1(C)C.OC(=O)C[C@H](N)C(=O)N[C@H](C)C(=O)NC1C(C)(C)SC1(C)C NUFKRGBSZPCGQB-FLBSXDLDSA-N 0.000 description 3
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 3
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 3
- 239000004377 Alitame Substances 0.000 description 3
- 235000017060 Arachis glabrata Nutrition 0.000 description 3
- 244000105624 Arachis hypogaea Species 0.000 description 3
- 235000010777 Arachis hypogaea Nutrition 0.000 description 3
- 235000018262 Arachis monticola Nutrition 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 3
- 235000009025 Carya illinoensis Nutrition 0.000 description 3
- 244000068645 Carya illinoensis Species 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 235000007716 Citrus aurantium Nutrition 0.000 description 3
- 240000003791 Citrus myrtifolia Species 0.000 description 3
- 235000000228 Citrus myrtifolia Nutrition 0.000 description 3
- 235000016646 Citrus taiwanica Nutrition 0.000 description 3
- 240000000560 Citrus x paradisi Species 0.000 description 3
- 229920000742 Cotton Polymers 0.000 description 3
- 206010011224 Cough Diseases 0.000 description 3
- 206010012735 Diarrhoea Diseases 0.000 description 3
- 235000016623 Fragaria vesca Nutrition 0.000 description 3
- 240000009088 Fragaria x ananassa Species 0.000 description 3
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 3
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 3
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 244000235659 Rubus idaeus Species 0.000 description 3
- 239000004376 Sucralose Substances 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- 235000011941 Tilia x europaea Nutrition 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- 235000003095 Vaccinium corymbosum Nutrition 0.000 description 3
- 235000017537 Vaccinium myrtillus Nutrition 0.000 description 3
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 3
- 235000009392 Vitis Nutrition 0.000 description 3
- 241000219095 Vitis Species 0.000 description 3
- 235000009754 Vitis X bourquina Nutrition 0.000 description 3
- 235000012333 Vitis X labruscana Nutrition 0.000 description 3
- 240000006365 Vitis vinifera Species 0.000 description 3
- 235000014787 Vitis vinifera Nutrition 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 206010000059 abdominal discomfort Diseases 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 235000019409 alitame Nutrition 0.000 description 3
- 108010009985 alitame Proteins 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 235000021168 barbecue Nutrition 0.000 description 3
- 230000000975 bioactive effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 235000021014 blueberries Nutrition 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 229960004106 citric acid Drugs 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 235000011950 custard Nutrition 0.000 description 3
- 239000013530 defoamer Substances 0.000 description 3
- 230000001627 detrimental effect Effects 0.000 description 3
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 238000005538 encapsulation Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229960000304 folic acid Drugs 0.000 description 3
- 235000019152 folic acid Nutrition 0.000 description 3
- 239000011724 folic acid Substances 0.000 description 3
- 239000003349 gelling agent Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 235000008216 herbs Nutrition 0.000 description 3
- 235000015243 ice cream Nutrition 0.000 description 3
- 206010022000 influenza Diseases 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 3
- 229960000310 isoleucine Drugs 0.000 description 3
- 230000002045 lasting effect Effects 0.000 description 3
- 229960003136 leucine Drugs 0.000 description 3
- 229960003646 lysine Drugs 0.000 description 3
- 235000013372 meat Nutrition 0.000 description 3
- 229930182817 methionine Natural products 0.000 description 3
- 229960004452 methionine Drugs 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 150000002772 monosaccharides Chemical group 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 235000020232 peanut Nutrition 0.000 description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 3
- 229960005190 phenylalanine Drugs 0.000 description 3
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 3
- 239000004302 potassium sorbate Substances 0.000 description 3
- 235000010241 potassium sorbate Nutrition 0.000 description 3
- 229940069338 potassium sorbate Drugs 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 239000006041 probiotic Substances 0.000 description 3
- 230000000529 probiotic effect Effects 0.000 description 3
- 235000018291 probiotics Nutrition 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 102220201076 rs201475876 Human genes 0.000 description 3
- 239000001509 sodium citrate Substances 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 235000019408 sucralose Nutrition 0.000 description 3
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 3
- 239000013589 supplement Substances 0.000 description 3
- 229960002898 threonine Drugs 0.000 description 3
- 229920000428 triblock copolymer Polymers 0.000 description 3
- 229960004799 tryptophan Drugs 0.000 description 3
- 229960004295 valine Drugs 0.000 description 3
- 239000004474 valine Substances 0.000 description 3
- 235000013311 vegetables Nutrition 0.000 description 3
- 239000000052 vinegar Substances 0.000 description 3
- 235000021419 vinegar Nutrition 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 2
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 2
- MEAPRSDUXBHXGD-UHFFFAOYSA-N 3-chloro-n-(4-propan-2-ylphenyl)propanamide Chemical compound CC(C)C1=CC=C(NC(=O)CCCl)C=C1 MEAPRSDUXBHXGD-UHFFFAOYSA-N 0.000 description 2
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 2
- 241000208140 Acer Species 0.000 description 2
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 2
- 240000002234 Allium sativum Species 0.000 description 2
- 244000144730 Amygdalus persica Species 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 235000018185 Betula X alpestris Nutrition 0.000 description 2
- 235000018212 Betula X uliginosa Nutrition 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- 235000004936 Bromus mango Nutrition 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 2
- 244000223760 Cinnamomum zeylanicum Species 0.000 description 2
- 235000013162 Cocos nucifera Nutrition 0.000 description 2
- 244000060011 Cocos nucifera Species 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 2
- 241000238557 Decapoda Species 0.000 description 2
- 239000004287 Dehydroacetic acid Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 241000287828 Gallus gallus Species 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229920002907 Guar gum Polymers 0.000 description 2
- 241000167880 Hirundinidae Species 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 101000801619 Homo sapiens Long-chain-fatty-acid-CoA ligase ACSBG1 Proteins 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 102100033564 Long-chain-fatty-acid-CoA ligase ACSBG1 Human genes 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 235000014826 Mangifera indica Nutrition 0.000 description 2
- 235000005135 Micromeria juliana Nutrition 0.000 description 2
- 241000581835 Monodora junodii Species 0.000 description 2
- 240000005561 Musa balbisiana Species 0.000 description 2
- 235000018290 Musa x paradisiaca Nutrition 0.000 description 2
- 239000004384 Neotame Substances 0.000 description 2
- 108010038807 Oligopeptides Proteins 0.000 description 2
- 102000015636 Oligopeptides Human genes 0.000 description 2
- 235000000370 Passiflora edulis Nutrition 0.000 description 2
- 244000288157 Passiflora edulis Species 0.000 description 2
- 235000011266 Passiflora quadrangularis Nutrition 0.000 description 2
- 244000179684 Passiflora quadrangularis Species 0.000 description 2
- 235000000556 Paullinia cupana Nutrition 0.000 description 2
- 240000003444 Paullinia cupana Species 0.000 description 2
- 235000004348 Perilla frutescens Nutrition 0.000 description 2
- 244000124853 Perilla frutescens Species 0.000 description 2
- 240000008474 Pimenta dioica Species 0.000 description 2
- 241001494501 Prosopis <angiosperm> Species 0.000 description 2
- 235000001560 Prosopis chilensis Nutrition 0.000 description 2
- 235000014460 Prosopis juliflora var juliflora Nutrition 0.000 description 2
- 235000013647 Prunus pensylvanica Nutrition 0.000 description 2
- 240000007942 Prunus pensylvanica Species 0.000 description 2
- 235000006040 Prunus persica var persica Nutrition 0.000 description 2
- 244000017714 Prunus persica var. nucipersica Species 0.000 description 2
- 235000014441 Prunus serotina Nutrition 0.000 description 2
- 244000294611 Punica granatum Species 0.000 description 2
- 235000014360 Punica granatum Nutrition 0.000 description 2
- 241000220324 Pyrus Species 0.000 description 2
- 240000001890 Ribes hudsonianum Species 0.000 description 2
- 235000016954 Ribes hudsonianum Nutrition 0.000 description 2
- 235000001466 Ribes nigrum Nutrition 0.000 description 2
- 235000011034 Rubus glaucus Nutrition 0.000 description 2
- 235000009122 Rubus idaeus Nutrition 0.000 description 2
- 241001125048 Sardina Species 0.000 description 2
- 235000007315 Satureja hortensis Nutrition 0.000 description 2
- 240000002114 Satureja hortensis Species 0.000 description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 2
- RJFAYQIBOAGBLC-BYPYZUCNSA-N Selenium-L-methionine Chemical compound C[Se]CC[C@H](N)C(O)=O RJFAYQIBOAGBLC-BYPYZUCNSA-N 0.000 description 2
- 235000008981 Smilax officinalis Nutrition 0.000 description 2
- 240000002493 Smilax officinalis Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 235000009184 Spondias indica Nutrition 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 240000004584 Tamarindus indica Species 0.000 description 2
- 235000004298 Tamarindus indica Nutrition 0.000 description 2
- BGNXCDMCOKJUMV-UHFFFAOYSA-N Tert-Butylhydroquinone Chemical compound CC(C)(C)C1=CC(O)=CC=C1O BGNXCDMCOKJUMV-UHFFFAOYSA-N 0.000 description 2
- 235000009470 Theobroma cacao Nutrition 0.000 description 2
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 2
- 235000002118 Vaccinium oxycoccus Nutrition 0.000 description 2
- 244000291414 Vaccinium oxycoccus Species 0.000 description 2
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 2
- 229930003268 Vitamin C Natural products 0.000 description 2
- 229930003427 Vitamin E Natural products 0.000 description 2
- 229920002000 Xyloglucan Polymers 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 235000006886 Zingiber officinale Nutrition 0.000 description 2
- 244000273928 Zingiber officinale Species 0.000 description 2
- 235000010358 acesulfame potassium Nutrition 0.000 description 2
- 239000000619 acesulfame-K Substances 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 230000036783 anaphylactic response Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 229960004543 anhydrous citric acid Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 235000015241 bacon Nutrition 0.000 description 2
- 235000012019 baked potatoes Nutrition 0.000 description 2
- 238000003287 bathing Methods 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 235000013532 brandy Nutrition 0.000 description 2
- 235000010634 bubble gum Nutrition 0.000 description 2
- 235000015155 buttermilk Nutrition 0.000 description 2
- 235000020289 caffè mocha Nutrition 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000007910 chewable tablet Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229910052804 chromium Inorganic materials 0.000 description 2
- 239000011651 chromium Substances 0.000 description 2
- 235000017803 cinnamon Nutrition 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N ***e Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 235000020186 condensed milk Nutrition 0.000 description 2
- 229920002770 condensed tannin Polymers 0.000 description 2
- 235000014510 cooky Nutrition 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 235000013365 dairy product Nutrition 0.000 description 2
- 235000019258 dehydroacetic acid Nutrition 0.000 description 2
- 229940061632 dehydroacetic acid Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003792 electrolyte Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 235000015244 frankfurter Nutrition 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 2
- 235000004611 garlic Nutrition 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 235000008397 ginger Nutrition 0.000 description 2
- 235000014080 ginger ale Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- 235000010417 guar gum Nutrition 0.000 description 2
- 239000000665 guar gum Substances 0.000 description 2
- 229960002154 guar gum Drugs 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 235000012907 honey Nutrition 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 235000015122 lemonade Nutrition 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 229940091250 magnesium supplement Drugs 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 2
- 239000004531 microgranule Substances 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 235000013379 molasses Nutrition 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 238000011328 necessary treatment Methods 0.000 description 2
- 235000019412 neotame Nutrition 0.000 description 2
- HLIAVLHNDJUHFG-HOTGVXAUSA-N neotame Chemical compound CC(C)(C)CCN[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 HLIAVLHNDJUHFG-HOTGVXAUSA-N 0.000 description 2
- 108010070257 neotame Proteins 0.000 description 2
- 229960002715 nicotine Drugs 0.000 description 2
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 239000002417 nutraceutical Substances 0.000 description 2
- 235000021436 nutraceutical agent Nutrition 0.000 description 2
- 235000014571 nuts Nutrition 0.000 description 2
- 235000019629 palatability Nutrition 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000006069 physical mixture Substances 0.000 description 2
- 235000017807 phytochemicals Nutrition 0.000 description 2
- 238000011020 pilot scale process Methods 0.000 description 2
- 235000020461 pink lemonade Nutrition 0.000 description 2
- 229930000223 plant secondary metabolite Natural products 0.000 description 2
- 239000000955 prescription drug Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 229960004604 propranolol hydrochloride Drugs 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol hydrochloride Natural products C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000001172 regenerating effect Effects 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 235000019192 riboflavin Nutrition 0.000 description 2
- 229960002477 riboflavin Drugs 0.000 description 2
- 239000002151 riboflavin Substances 0.000 description 2
- 229940085605 saccharin sodium Drugs 0.000 description 2
- WVYADZUPLLSGPU-UHFFFAOYSA-N salsalate Chemical compound OC(=O)C1=CC=CC=C1OC(=O)C1=CC=CC=C1O WVYADZUPLLSGPU-UHFFFAOYSA-N 0.000 description 2
- 235000014102 seafood Nutrition 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 239000011669 selenium Substances 0.000 description 2
- 229960002718 selenomethionine Drugs 0.000 description 2
- 230000014860 sensory perception of taste Effects 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- 239000000779 smoke Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229940083542 sodium Drugs 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000008279 sol Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 235000019157 thiamine Nutrition 0.000 description 2
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 2
- 229960003495 thiamine Drugs 0.000 description 2
- 239000011721 thiamine Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 229930003799 tocopherol Natural products 0.000 description 2
- 229960001295 tocopherol Drugs 0.000 description 2
- 235000010384 tocopherol Nutrition 0.000 description 2
- 239000011732 tocopherol Substances 0.000 description 2
- 229910052720 vanadium Inorganic materials 0.000 description 2
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 description 2
- 235000020047 vermouth Nutrition 0.000 description 2
- 235000019155 vitamin A Nutrition 0.000 description 2
- 239000011719 vitamin A Substances 0.000 description 2
- 235000019154 vitamin C Nutrition 0.000 description 2
- 239000011718 vitamin C Substances 0.000 description 2
- 235000019165 vitamin E Nutrition 0.000 description 2
- 239000011709 vitamin E Substances 0.000 description 2
- 229940046009 vitamin E Drugs 0.000 description 2
- 229940045997 vitamin a Drugs 0.000 description 2
- 235000015041 whisky Nutrition 0.000 description 2
- 235000010493 xanthan gum Nutrition 0.000 description 2
- 239000000230 xanthan gum Substances 0.000 description 2
- 229940082509 xanthan gum Drugs 0.000 description 2
- 235000013618 yogurt Nutrition 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-M (E,E)-sorbate Chemical compound C\C=C\C=C\C([O-])=O WSWCOQWTEOXDQX-MQQKCMAXSA-M 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- HXRSXEDVVARPHP-UDWIEESQSA-N (z)-1-n'-(1,3-benzodioxol-5-ylmethyl)-1-n-[2-[[5-[(dimethylamino)methyl]furan-2-yl]methylsulfanyl]ethyl]-2-nitroethene-1,1-diamine Chemical compound O1C(CN(C)C)=CC=C1CSCCN\C(=C/[N+]([O-])=O)NCC1=CC=C(OCO2)C2=C1 HXRSXEDVVARPHP-UDWIEESQSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- KEDVUOWPLAHMLZ-UHFFFAOYSA-N 1-cyano-3-[2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]ethyl]-2-prop-2-ynylguanidine Chemical compound CC=1NC=NC=1CSCCNC(NC#N)=NCC#C KEDVUOWPLAHMLZ-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- ADVGKWPZRIDURE-UHFFFAOYSA-N 2'-Hydroxyacetanilide Chemical compound CC(=O)NC1=CC=CC=C1O ADVGKWPZRIDURE-UHFFFAOYSA-N 0.000 description 1
- AMOYMEBHYUTMKJ-UHFFFAOYSA-N 2-(2-phenylethoxy)ethylbenzene Chemical compound C=1C=CC=CC=1CCOCCC1=CC=CC=C1 AMOYMEBHYUTMKJ-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- FEBUJFMRSBAMES-UHFFFAOYSA-N 2-[(2-{[3,5-dihydroxy-2-(hydroxymethyl)-6-phosphanyloxan-4-yl]oxy}-3,5-dihydroxy-6-({[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}methyl)oxan-4-yl)oxy]-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl phosphinite Chemical compound OC1C(O)C(O)C(CO)OC1OCC1C(O)C(OC2C(C(OP)C(O)C(CO)O2)O)C(O)C(OC2C(C(CO)OC(P)C2O)O)O1 FEBUJFMRSBAMES-UHFFFAOYSA-N 0.000 description 1
- FEDJGPQLLNQAIY-UHFFFAOYSA-N 2-[(6-oxo-1h-pyridazin-3-yl)oxy]acetic acid Chemical compound OC(=O)COC=1C=CC(=O)NN=1 FEDJGPQLLNQAIY-UHFFFAOYSA-N 0.000 description 1
- CZTPLYMKHNEVHO-UHFFFAOYSA-N 2-[2-[[5-(2-aminopropan-2-yl)furan-2-yl]methylsulfanyl]ethylamino]-5-[(6-methylpyridin-3-yl)methyl]-1h-pyrimidin-6-one Chemical compound C1=NC(C)=CC=C1CC(C(N1)=O)=CN=C1NCCSCC1=CC=C(C(C)(C)N)O1 CZTPLYMKHNEVHO-UHFFFAOYSA-N 0.000 description 1
- GIMNAEMRNXUAQP-UHFFFAOYSA-N 2-[4-(2-methyl-1h-imidazol-5-yl)-1,3-thiazol-2-yl]guanidine Chemical compound N1C(C)=NC=C1C1=CSC(N=C(N)N)=N1 GIMNAEMRNXUAQP-UHFFFAOYSA-N 0.000 description 1
- FSWCCDQGXZITPD-UHFFFAOYSA-N 2-[4-[2-[(5-amino-4-methyl-1,1-dioxo-1,2,4,6-thiatriazin-3-yl)amino]ethylsulfanylmethyl]-1,3-thiazol-2-yl]guanidine Chemical compound CN1C(N)=NS(=O)(=O)N=C1NCCSCC1=CSC(N=C(N)N)=N1 FSWCCDQGXZITPD-UHFFFAOYSA-N 0.000 description 1
- UBDZFAGVPPMTIT-UHFFFAOYSA-N 2-aminoguanidine;hydron;chloride Chemical compound [Cl-].NC(N)=N[NH3+] UBDZFAGVPPMTIT-UHFFFAOYSA-N 0.000 description 1
- SPCKHVPPRJWQRZ-UHFFFAOYSA-N 2-benzhydryloxy-n,n-dimethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 SPCKHVPPRJWQRZ-UHFFFAOYSA-N 0.000 description 1
- AZJQQNWSSLCLJN-UHFFFAOYSA-N 2-ethoxyquinoline Chemical compound C1=CC=CC2=NC(OCC)=CC=C21 AZJQQNWSSLCLJN-UHFFFAOYSA-N 0.000 description 1
- YSLIPUSJNFIFAB-UHFFFAOYSA-N 2-oxopyridine-1-carboxylic acid Chemical compound OC(=O)N1C=CC=CC1=O YSLIPUSJNFIFAB-UHFFFAOYSA-N 0.000 description 1
- SQVIAVUSQAWMKL-UHFFFAOYSA-N 3-[2-(ethylamino)-1-hydroxyethyl]phenol Chemical compound CCNCC(O)C1=CC=CC(O)=C1 SQVIAVUSQAWMKL-UHFFFAOYSA-N 0.000 description 1
- DBTMGCOVALSLOR-UHFFFAOYSA-N 32-alpha-galactosyl-3-alpha-galactosyl-galactose Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(OC2C(C(CO)OC(O)C2O)O)OC(CO)C1O DBTMGCOVALSLOR-UHFFFAOYSA-N 0.000 description 1
- GLQPTZAAUROJMO-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)benzaldehyde Chemical compound C1=C(OC)C(OC)=CC=C1C1=CC=C(C=O)C=C1 GLQPTZAAUROJMO-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- 235000009434 Actinidia chinensis Nutrition 0.000 description 1
- 244000298697 Actinidia deliciosa Species 0.000 description 1
- 235000009436 Actinidia deliciosa Nutrition 0.000 description 1
- 244000198134 Agave sisalana Species 0.000 description 1
- 235000011624 Agave sisalana Nutrition 0.000 description 1
- 241001116389 Aloe Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 244000208874 Althaea officinalis Species 0.000 description 1
- 235000006576 Althaea officinalis Nutrition 0.000 description 1
- 229920000945 Amylopectin Polymers 0.000 description 1
- 240000007087 Apium graveolens Species 0.000 description 1
- 235000015849 Apium graveolens Dulce Group Nutrition 0.000 description 1
- 235000010591 Appio Nutrition 0.000 description 1
- VKJGBAJNNALVAV-UHFFFAOYSA-M Berberine chloride (TN) Chemical compound [Cl-].C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 VKJGBAJNNALVAV-UHFFFAOYSA-M 0.000 description 1
- 206010004542 Bezoar Diseases 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- 235000002566 Capsicum Nutrition 0.000 description 1
- 235000008534 Capsicum annuum var annuum Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 235000009467 Carica papaya Nutrition 0.000 description 1
- 240000006432 Carica papaya Species 0.000 description 1
- 241000723418 Carya Species 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
- 102000009660 Cholinergic Receptors Human genes 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 244000037364 Cinnamomum aromaticum Species 0.000 description 1
- 235000014489 Cinnamomum aromaticum Nutrition 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- 241000219109 Citrullus Species 0.000 description 1
- 235000012828 Citrullus lanatus var citroides Nutrition 0.000 description 1
- 244000270200 Citrullus vulgaris Species 0.000 description 1
- 235000012840 Citrullus vulgaris Nutrition 0.000 description 1
- 241000252203 Clupea harengus Species 0.000 description 1
- 241001454694 Clupeiformes Species 0.000 description 1
- 241000825055 Coilia Species 0.000 description 1
- 235000010205 Cola acuminata Nutrition 0.000 description 1
- 235000015438 Cola nitida Nutrition 0.000 description 1
- 241000350000 Colophospermum mopane Species 0.000 description 1
- 240000003890 Commiphora wightii Species 0.000 description 1
- 241000949463 Correa reflexa Species 0.000 description 1
- 240000009226 Corylus americana Species 0.000 description 1
- 235000001543 Corylus americana Nutrition 0.000 description 1
- 235000007466 Corylus avellana Nutrition 0.000 description 1
- 235000015001 Cucumis melo var inodorus Nutrition 0.000 description 1
- 240000002495 Cucumis melo var. inodorus Species 0.000 description 1
- 240000008067 Cucumis sativus Species 0.000 description 1
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 description 1
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RXVWSYJTUUKTEA-UHFFFAOYSA-N D-maltotriose Natural products OC1C(O)C(OC(C(O)CO)C(O)C(O)C=O)OC(CO)C1OC1C(O)C(O)C(O)C(CO)O1 RXVWSYJTUUKTEA-UHFFFAOYSA-N 0.000 description 1
- 244000000626 Daucus carota Species 0.000 description 1
- 235000002767 Daucus carota Nutrition 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- WDJUZGPOPHTGOT-OAXVISGBSA-N Digitoxin Natural products O([C@H]1[C@@H](C)O[C@@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@@](C)([C@H](C6=CC(=O)OC6)CC5)CC4)CC3)CC2)C[C@H]1O)[C@H]1O[C@@H](C)[C@H](O[C@H]2O[C@@H](C)[C@@H](O)[C@@H](O)C2)[C@@H](O)C1 WDJUZGPOPHTGOT-OAXVISGBSA-N 0.000 description 1
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- KBAUFVUYFNWQFM-UHFFFAOYSA-N Doxylamine succinate Chemical compound OC(=O)CCC(O)=O.C=1C=CC=NC=1C(C)(OCCN(C)C)C1=CC=CC=C1 KBAUFVUYFNWQFM-UHFFFAOYSA-N 0.000 description 1
- 206010013911 Dysgeusia Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010053155 Epigastric discomfort Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 240000001238 Gaultheria procumbens Species 0.000 description 1
- 235000007297 Gaultheria procumbens Nutrition 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 description 1
- ZTJORNVITHUQJA-UHFFFAOYSA-N Heptyl p-hydroxybenzoate Chemical compound CCCCCCCOC(=O)C1=CC=C(O)C=C1 ZTJORNVITHUQJA-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- MADRVGBADLFHMO-UHFFFAOYSA-N Indeloxazine Chemical compound C=1C=CC=2C=CCC=2C=1OCC1CNCCO1 MADRVGBADLFHMO-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022004 Influenza like illness Diseases 0.000 description 1
- 240000007049 Juglans regia Species 0.000 description 1
- 235000009496 Juglans regia Nutrition 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000017858 Laurus nobilis Nutrition 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 229920000161 Locust bean gum Polymers 0.000 description 1
- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 description 1
- JEVVKJMRZMXFBT-XWDZUXABSA-N Lycophyll Natural products OC/C(=C/CC/C(=C\C=C\C(=C/C=C/C(=C\C=C\C=C(/C=C/C=C(\C=C\C=C(/CC/C=C(/CO)\C)\C)/C)\C)/C)\C)/C)/C JEVVKJMRZMXFBT-XWDZUXABSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- OCJYIGYOJCODJL-UHFFFAOYSA-N Meclizine Chemical compound CC1=CC=CC(CN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)=C1 OCJYIGYOJCODJL-UHFFFAOYSA-N 0.000 description 1
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 235000014749 Mentha crispa Nutrition 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000016247 Mentha requienii Nutrition 0.000 description 1
- 240000003321 Mentha requienii Species 0.000 description 1
- 244000078639 Mentha spicata Species 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- 235000008708 Morus alba Nutrition 0.000 description 1
- 240000000249 Morus alba Species 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 244000227633 Ocotea pretiosa Species 0.000 description 1
- 235000004263 Ocotea pretiosa Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000006002 Pepper Substances 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 241000218657 Picea Species 0.000 description 1
- 235000006990 Pimenta dioica Nutrition 0.000 description 1
- 235000016761 Piper aduncum Nutrition 0.000 description 1
- 240000003889 Piper guineense Species 0.000 description 1
- 235000017804 Piper guineense Nutrition 0.000 description 1
- 235000008184 Piper nigrum Nutrition 0.000 description 1
- VQDBNKDJNJQRDG-UHFFFAOYSA-N Pirbuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=N1 VQDBNKDJNJQRDG-UHFFFAOYSA-N 0.000 description 1
- 235000003447 Pistacia vera Nutrition 0.000 description 1
- 240000006711 Pistacia vera Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- 235000009827 Prunus armeniaca Nutrition 0.000 description 1
- 244000018633 Prunus armeniaca Species 0.000 description 1
- 235000010401 Prunus avium Nutrition 0.000 description 1
- 235000006029 Prunus persica var nucipersica Nutrition 0.000 description 1
- 240000008296 Prunus serotina Species 0.000 description 1
- 241000508269 Psidium Species 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 235000014443 Pyrus communis Nutrition 0.000 description 1
- SMTZFNFIKUPEJC-UHFFFAOYSA-N Roxane Chemical compound CC(=O)OCC(=O)NCCCOC1=CC=CC(CN2CCCCC2)=C1 SMTZFNFIKUPEJC-UHFFFAOYSA-N 0.000 description 1
- 241001412173 Rubus canescens Species 0.000 description 1
- 235000003942 Rubus occidentalis Nutrition 0.000 description 1
- 244000111388 Rubus occidentalis Species 0.000 description 1
- 240000000203 Salix gracilistyla Species 0.000 description 1
- 229920002305 Schizophyllan Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000004283 Sodium sorbate Substances 0.000 description 1
- 235000017899 Spathodea campanulata Nutrition 0.000 description 1
- NKZMPZCWBSWAOX-IBTYICNHSA-M Sulbactam sodium Chemical compound [Na+].O=S1(=O)C(C)(C)[C@H](C([O-])=O)N2C(=O)C[C@H]21 NKZMPZCWBSWAOX-IBTYICNHSA-M 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 244000125380 Terminalia tomentosa Species 0.000 description 1
- 235000005212 Terminalia tomentosa Nutrition 0.000 description 1
- 235000007303 Thymus vulgaris Nutrition 0.000 description 1
- 240000002657 Thymus vulgaris Species 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 235000012545 Vaccinium macrocarpon Nutrition 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- JVFGXECLSQXABC-UHFFFAOYSA-N ac1l3obq Chemical compound O1C(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(O)C2O)C(COCC(O)C)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC2C(O)C(O)C1OC2COCC(C)O JVFGXECLSQXABC-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 235000011399 aloe vera Nutrition 0.000 description 1
- AGBQKNBQESQNJD-UHFFFAOYSA-N alpha-Lipoic acid Natural products OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 description 1
- 229960005174 ambroxol Drugs 0.000 description 1
- PECIYKGSSMCNHN-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=NC=N[C]21.O=C1N(C)C(=O)N(C)C2=NC=N[C]21 PECIYKGSSMCNHN-UHFFFAOYSA-N 0.000 description 1
- 229960003556 aminophylline Drugs 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 description 1
- 229960004005 amlodipine besylate Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
- 239000004004 anti-anginal agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003627 anti-cholesterol Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940125713 antianxiety drug Drugs 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940124623 antihistamine drug Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- 235000021420 balsamic vinegar Nutrition 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 1
- 239000004301 calcium benzoate Substances 0.000 description 1
- 235000010237 calcium benzoate Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229960002079 calcium pantothenate Drugs 0.000 description 1
- MCFVRESNTICQSJ-RJNTXXOISA-L calcium sorbate Chemical compound [Ca+2].C\C=C\C=C\C([O-])=O.C\C=C\C=C\C([O-])=O MCFVRESNTICQSJ-RJNTXXOISA-L 0.000 description 1
- 235000010244 calcium sorbate Nutrition 0.000 description 1
- 239000004303 calcium sorbate Substances 0.000 description 1
- HZQXCUSDXIKLGS-UHFFFAOYSA-L calcium;dibenzoate;trihydrate Chemical compound O.O.O.[Ca+2].[O-]C(=O)C1=CC=CC=C1.[O-]C(=O)C1=CC=CC=C1 HZQXCUSDXIKLGS-UHFFFAOYSA-L 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000002371 cardiac agent Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 241001233037 catfish Species 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 229940106164 cephalexin Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000020104 cherry wine Nutrition 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229960004782 chlordiazepoxide Drugs 0.000 description 1
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 1
- 229940097572 chloromycetin Drugs 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000019506 cigar Nutrition 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 235000020965 cold beverage Nutrition 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000010219 correlation analysis Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 235000004634 cranberry Nutrition 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 239000000850 decongestant Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940096516 dextrates Drugs 0.000 description 1
- 229960001985 dextromethorphan Drugs 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- WDJUZGPOPHTGOT-XUDUSOBPSA-N digitoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O WDJUZGPOPHTGOT-XUDUSOBPSA-N 0.000 description 1
- 229960000648 digitoxin Drugs 0.000 description 1
- 229960005156 digoxin Drugs 0.000 description 1
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 1
- QGGZBXOADPVUPN-UHFFFAOYSA-N dihydrochalcone Chemical compound C=1C=CC=CC=1C(=O)CCC1=CC=CC=C1 QGGZBXOADPVUPN-UHFFFAOYSA-N 0.000 description 1
- PXLWOFBAEVGBOA-UHFFFAOYSA-N dihydrochalcone Natural products OC1C(O)C(O)C(CO)OC1C1=C(O)C=CC(C(=O)CC(O)C=2C=CC(O)=CC=2)=C1O PXLWOFBAEVGBOA-UHFFFAOYSA-N 0.000 description 1
- 229960005316 diltiazem hydrochloride Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- HYPPXZBJBPSRLK-UHFFFAOYSA-N diphenoxylate Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 HYPPXZBJBPSRLK-UHFFFAOYSA-N 0.000 description 1
- 229940120889 dipyrone Drugs 0.000 description 1
- NLLGJEMIZSAJFN-AAFOHLTDSA-L disodium;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxy-1-[4-[4-[[(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxy-1-sulfonatohexyl]amino]phenyl]sulfonylanilino]hexane-1-sulfonate Chemical group [Na+].[Na+].C1=CC(NC([C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)S([O-])(=O)=O)=CC=C1S(=O)(=O)C1=CC=C(NC([C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)S([O-])(=O)=O)C=C1 NLLGJEMIZSAJFN-AAFOHLTDSA-L 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 1
- 229960005008 doxylamine succinate Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000005868 electrolysis reaction Methods 0.000 description 1
- 229960002472 eletriptan Drugs 0.000 description 1
- OTLDLQZJRFYOJR-LJQANCHMSA-N eletriptan Chemical compound CN1CCC[C@@H]1CC1=CN=C2[C]1C=C(CCS(=O)(=O)C=1C=CC=CC=1)C=C2 OTLDLQZJRFYOJR-LJQANCHMSA-N 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 229960002549 enoxacin Drugs 0.000 description 1
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 229950007285 etintidine Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960001596 famotidine Drugs 0.000 description 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000005429 filling process Methods 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 206010016766 flatulence Diseases 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 235000007983 food acid Nutrition 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 239000000989 food dye Substances 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 235000012027 fruit salads Nutrition 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 235000021474 generally recognized As safe (food) Nutrition 0.000 description 1
- 235000021473 generally recognized as safe (food ingredients) Nutrition 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 229950009858 glucosulfone Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 239000000745 gonadal hormone Substances 0.000 description 1
- 235000015810 grayleaf red raspberry Nutrition 0.000 description 1
- 235000009569 green tea Nutrition 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229960002146 guaifenesin Drugs 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000037219 healthy weight Effects 0.000 description 1
- 208000024798 heartburn Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 229960005236 ibandronic acid Drugs 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229960004333 indeloxazine Drugs 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 235000019223 lemon-lime Nutrition 0.000 description 1
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 235000020094 liqueur Nutrition 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 235000010420 locust bean gum Nutrition 0.000 description 1
- 239000000711 locust bean gum Substances 0.000 description 1
- 229940087973 lomotil Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 229950000367 lupitidine Drugs 0.000 description 1
- 235000012661 lycopene Nutrition 0.000 description 1
- 229960004999 lycopene Drugs 0.000 description 1
- OAIJSZIZWZSQBC-GYZMGTAESA-N lycopene Chemical compound CC(C)=CCC\C(C)=C\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C=C(/C)CCC=C(C)C OAIJSZIZWZSQBC-GYZMGTAESA-N 0.000 description 1
- 239000001751 lycopene Substances 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 235000020162 malted milk drink Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- FYGDTMLNYKFZSV-UHFFFAOYSA-N mannotriose Natural products OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(OC2C(OC(O)C(O)C2O)CO)C(O)C1O FYGDTMLNYKFZSV-UHFFFAOYSA-N 0.000 description 1
- 235000001035 marshmallow Nutrition 0.000 description 1
- 229960001474 meclozine Drugs 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- 229960003987 melatonin Drugs 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- DJGAAPFSPWAYTJ-UHFFFAOYSA-M metamizole sodium Chemical compound [Na+].O=C1C(N(CS([O-])(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 DJGAAPFSPWAYTJ-UHFFFAOYSA-M 0.000 description 1
- NZWOPGCLSHLLPA-UHFFFAOYSA-N methacholine Chemical compound C[N+](C)(C)CC(C)OC(C)=O NZWOPGCLSHLLPA-UHFFFAOYSA-N 0.000 description 1
- 229960002329 methacholine Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 235000020166 milkshake Nutrition 0.000 description 1
- 229940029985 mineral supplement Drugs 0.000 description 1
- 235000020786 mineral supplement Nutrition 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- ARGKVCXINMKCAZ-UZRWAPQLSA-N neohesperidin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O[C@H]3[C@@H]([C@H](O)[C@@H](O)[C@H](C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UZRWAPQLSA-N 0.000 description 1
- ARGKVCXINMKCAZ-UHFFFAOYSA-N neohesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(CO)O3)OC3C(C(O)C(O)C(C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UHFFFAOYSA-N 0.000 description 1
- 229960002362 neostigmine Drugs 0.000 description 1
- LULNWZDBKTWDGK-UHFFFAOYSA-M neostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 LULNWZDBKTWDGK-UHFFFAOYSA-M 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 229960001323 niperotidine Drugs 0.000 description 1
- 229960004872 nizatidine Drugs 0.000 description 1
- SGXXNSQHWDMGGP-IZZDOVSWSA-N nizatidine Chemical compound [O-][N+](=O)\C=C(/NC)NCCSCC1=CSC(CN(C)C)=N1 SGXXNSQHWDMGGP-IZZDOVSWSA-N 0.000 description 1
- 239000011356 non-aqueous organic solvent Substances 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 235000015205 orange juice Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 210000003695 paranasal sinus Anatomy 0.000 description 1
- 235000021017 pears Nutrition 0.000 description 1
- 229960004236 pefloxacin Drugs 0.000 description 1
- FHFYDNQZQSQIAI-UHFFFAOYSA-N pefloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 FHFYDNQZQSQIAI-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000001175 peptic effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000079 pharmacotherapeutic effect Effects 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229960001732 pipemidic acid Drugs 0.000 description 1
- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 description 1
- 229960005414 pirbuterol Drugs 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 235000020233 pistachio Nutrition 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 235000002378 plant sterols Nutrition 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000447 polyanionic polymer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000004300 potassium benzoate Substances 0.000 description 1
- 235000010235 potassium benzoate Nutrition 0.000 description 1
- 229940103091 potassium benzoate Drugs 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012713 reactive precursor Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 235000021572 root beer Nutrition 0.000 description 1
- 229960003320 roxatidine Drugs 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 229960000953 salsalate Drugs 0.000 description 1
- 235000020050 sangria Nutrition 0.000 description 1
- 235000019512 sardine Nutrition 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229960003660 sertraline hydrochloride Drugs 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 230000005586 smoking cessation Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960001462 sodium cyclamate Drugs 0.000 description 1
- 235000019982 sodium hexametaphosphate Nutrition 0.000 description 1
- LROWVYNUWKVTCU-STWYSWDKSA-M sodium sorbate Chemical compound [Na+].C\C=C\C=C\C([O-])=O LROWVYNUWKVTCU-STWYSWDKSA-M 0.000 description 1
- 235000019250 sodium sorbate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 229940075554 sorbate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000015040 sparkling wine Nutrition 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 235000020354 squash Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 229960000614 sulbactam sodium Drugs 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 125000004964 sulfoalkyl group Chemical group 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- OPYGFNJSCUDTBT-PMLPCWDUSA-N sultamicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(=O)OCOC(=O)[C@H]2C(S(=O)(=O)[C@H]3N2C(C3)=O)(C)C)(C)C)=CC=CC=C1 OPYGFNJSCUDTBT-PMLPCWDUSA-N 0.000 description 1
- 229960001326 sultamicillin Drugs 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- 229960003676 tenidap Drugs 0.000 description 1
- LXIKEPCNDFVJKC-QXMHVHEDSA-N tenidap Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 LXIKEPCNDFVJKC-QXMHVHEDSA-N 0.000 description 1
- 235000013529 tequila Nutrition 0.000 description 1
- 229960000351 terfenadine Drugs 0.000 description 1
- 239000004250 tert-Butylhydroquinone Substances 0.000 description 1
- 235000019281 tert-butylhydroquinone Nutrition 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- 239000001585 thymus vulgaris Substances 0.000 description 1
- 235000015149 toffees Nutrition 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- ZCIHMQAPACOQHT-ZGMPDRQDSA-N trans-isorenieratene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/c1c(C)ccc(C)c1C)C=CC=C(/C)C=Cc2c(C)ccc(C)c2C ZCIHMQAPACOQHT-ZGMPDRQDSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 229950010224 tuvatidine Drugs 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 235000019195 vitamin supplement Nutrition 0.000 description 1
- 235000020234 walnut Nutrition 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 235000020795 whole food diet Nutrition 0.000 description 1
- 230000003245 working effect Effects 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229950003675 zaltidine Drugs 0.000 description 1
- 229960002911 zonisamide Drugs 0.000 description 1
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 1
- FYGDTMLNYKFZSV-BYLHFPJWSA-N β-1,4-galactotrioside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@H](CO)O[C@@H](O[C@@H]2[C@@H](O[C@@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-BYLHFPJWSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/84—Flavour masking or reducing agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/465—Nicotine; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nutrition Science (AREA)
- Polymers & Plastics (AREA)
- Food Science & Technology (AREA)
- Molecular Biology (AREA)
- Pain & Pain Management (AREA)
- Inorganic Chemistry (AREA)
- Nanotechnology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
- Crystallography & Structural Chemistry (AREA)
- Biophysics (AREA)
- Biotechnology (AREA)
- Neurology (AREA)
- Rheumatology (AREA)
- Neurosurgery (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Biomedical Technology (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Non-Alcoholic Beverages (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Novel water stable pharmaceutical compositions, their liquid form oral pharmaceutical compositions and kits thereof, rehydration beverages containing these water stable pharmaceutical compositions methods of manufacture and methods of use thereof are disclosed. The novel aqueous delivery systems are useful, inter alia, as alternative pharmaceutical dosing agents to tablets, capsules and other forms of delivering medication to a mammalian host in need thereof.
Description
The cross reference of related application
13/231,150 the priority that the application requires that number 61/382,098 and 2011 year JIUYUE of U. S. application that JIUYUE in 2010 submitted on the 13rd submitted on the 13rd is introduced the application as a reference with these documents are whole.
Technical field
The present invention relates to the water stability pharmaceutical composition, their liquid dosage form and their preparation method.More specifically, the present invention relates in the presence of abnormal flavour screening agent (off-flavor masking agent) and water stability medicinal substrate, comprise the pharmaceutical composition of therapeutic agent, and their aqueous dosage forms.More specifically, the present invention relates in the presence of abnormal flavour screening agent and water stability medicinal substrate, comprise usually the pharmaceutical composition of water sensitivity therapeutic agent, and their aqueous dosage forms.Part is owing to the reactivity of the water sensitivity therapeutic agent in the drug system of the present invention when being exposed to aqueous environment reduces, and these compositionss can be particularly useful for the liquid delivery system of therapeutic agent.
Background technology
Drug products designs at three class individualities at present: baby, child and adult.Baby's demand is different with 2 to 12 years old child, and child's demand is different with the adult.And the demand of elderly population is different from other adult.The another kind of individuality that needs the alternative drugs delivery form is the patient who carries out the long-term dosage scheme.Repeat administration tablet or pill bring problem may for the patient with daily dose scheme demand.Therefore, need substituting dosage form for multiple patient crowd.
Pediatric patients has dysphagia, reaches the age in about 10-16 year up to them.The conventional tablet that the less pediatric patients of age is taken chewable tablets usually, used food/fruit juice to pulverize and mix, or take liquid dosage form.Chewable tablets is generally good dosage form, and it can not fully cover the taste of activating agent sometimes.It is consuming time, trouble pulverizing and mix conventional tablet with food or fruit juice, and is unpractical sometimes.The liquid dosage form for example difficulty of syrup is, they are bulky, and mouthfeel is bad sometimes, and compares potentially unstable with solid dosage forms such as tablet.Practical and novel dosage form will be valuable for these patients.
Along with the progress of medical science with to the concern of healthy Lifestyle, in the U.S. and other countries' aging population outstanding growth is arranged.At present, among the American 65 years old or older people take in the prescription drug near 30%.And the expection old people can increase for the demand of medicine.Although in the old people, for prescription drug out-of-proportion big demand is arranged, pay close attention to less at the pharmacotherapeutics demand of the uniqueness of this age groups.
Many gerontal patients have any problem when swallow tablet or capsule, yet the most of dosage forms that deliver medicine to the old people are tablet or capsule.The tablet of coating is convenient in the preparation and economical, but often is difficult to swallow and usually because " hanging and " cause discomfort in throat.The tablet of coating and capsule are easier to swallow to a certain extent, but along with the age increases and to deliver medicine to the medicine number of independent part too big, it also causes people's worry.Liquid dosage form more easily gives, but comparatively expensive, is easy to spill, and often mouthfeel is bad, and every dosage unit occupies larger volume, and has stability problem.
With respect to solid oral dosage form, the obvious advantage that liquid preparation has dosage flexibly and conveniently swallows.The unit dose that is equivalent to a plurality of capsules or tablet can administration in the liquid of the least possible single volume.And, be recognized that needs can be by the preparation of the liquid dosage form form acquisition that makes things convenient for, is easy to take.Yet, up to now, provide chemical stability in the prior art, and therefore the commercial liquid oral suspension formulations that has enough shelf lives (for the water sensitivity therapeutic agent in the aqueous compositions) only obtains limited success.The fluid product of commericially feasible, especially liquid, aqueous product, the stability of the therapeutic agent that exists in the needs maintenance liquid dispersion system provides the release profile from decentralized photo suitable or that improve when therapeutic agent absorbs, and the free drug concentration in the restriction disperse medium.
The problem that the preparation of water sensitivity therapeutic agent exists is well-known.Usually, contact one or more chemical property or the function that influences medicine unfriendly with dampness or water, it is that part is important at least that this character or function are renderd a service for the treatment of medicine.For example, aspirin (acetylsalicylic acid) may be the most widely used medicine in the world, but its to the sensitivity of water and concurrent ester hydrolysis limited will deliver medicine to patient's aspirin can mode.Acetylsalicylic acid comparatively fast is hydrolyzed into salicylic acid and acetic acid in the presence of water.Be reported in and formed multiple other impurity in the hydrolytic process, comprised acetylsalicylic acid acid anhydride and acetyl group disalicylic acid.It is said that aspirin is caused its pharmacologically active that heavy losses are arranged by water decomposition.This decomposition is limited to the solid preparation form with the sale of acetylsalicylic acid, and is all the more so in particular for the preparation of myocardial infarction prevention.In principle, the solid Genprin can be only by oral administration, wherein fast decomposition/hydrolysis mainly in the sour environment of stomach, in the gastric mucosa absorption process and in liver, take place.Reported that oral administration causes following situation, wherein made an appointment with the acetylsalicylic acid of half to arrive blood flow (Burghart, US6,306,843) with its hydrolysed form.The hydrolyzate that forms in the process that aspirin is absorbed by the patient (salicylic acid) is indicated as and has encouraged side effect, for example, and gastrorrhagia; Cause sizable added burden with the excessive dosage that needs in the quick degraded of absorption process because of aspirin to the patient.
Some researcheres have attempted making water sensitivity treatment chemical compound to hydrolysis-stable.For example, Galat (US5,776,431) some solid composite with the aspirin of some alkali compoundss combination is disclosed, it was reported that show instable other prior art solid composite than the water to hydration, the described compositions of powder type is to hydrolysis-stable.Galat has reported that also its solid composite is soluble in water, but he does not test or mention whether his compositions is stable in time in water-bearing media.
Other people have attempted reducing hydrolysis in the solid composite by coating or encapsulation therapeutic agent.For example, people such as Burgguiere (US5,846,566) disclosed the aspirin granule of some coatings, wherein said coating materials is made up of coated composition, and described coated composition comprises: at least a at the insoluble film forming polymer of gastroenteric environment, at least a water-soluble polymer, at least a solid lubrication filler and at least a hydrophobic plasticizer.Vachon and Nairn (J.Microencapsulation, 14 (3), 281-301,1997) some the aspirin microspheres by some acrylate copolymer/non-aqueous solution preparation have been described, and described aspirin and gone through 24 hours from the release of described microsphere.
Other people propose substrate is used for the treatment of sending of agent.For example, Malmsten (Soft Matter2,760-769,2000) discloses substantially to use and has comprised that the soft drug delivery system of polymer and/or polysaccharide gel is to provide therapeutic agent to the patient.
Harel (US2008/0044481) discloses some and has comprised microballon of oil phase pass bioactive compound and its production and use.Described microballon is made up of the soluble complex of indigestible polymer and emulsifying agent, and wherein oil phase pass bioactive compound is embedded in the substrate that can digest polymer.
Agnihotri (European J.Pharmaceutics and Biopharmaceutics63,249-261 (2006)) studied the control of cefalexin by gelling carbohydrate gum (gellan gum) pearl and discharged, it is based on some formulation parameters such as pH, therapeutic agent load with in the presence of the actual mixt of calcium and zinc counter ion counterionsl gegenions.
People such as Kedzierewicz (Int.J.Pharmaceutics, 178,129-1361999) preparation of hydrophilic, water stability therapeutic agent propranolol hydrochloride and from the release of some gelling carbohydrate gum pearls is disclosed.
People such as McGurk (US7; 713; 551) solid or semi-solid gelatin nano-particle activating agent dosage form are disclosed; it comprises at least a nano-particle surfactant composition and at least a gel formation material, and described gel formation material is shaped and to be enough to keep the gelation of excessive water in solid or semi-solid gelatin form.It is said that described reagent composition needs activating agent and at least a absorption of at least a specified particle diameter or associates at the lip-deep surface stabilizer of activating agent.Report that these dosage forms have the advantage of the quick stripping of activating agent after the administration of being easy to and the administration.
By only using the non-liquid, aqueous trial of eliminating the hydrolysis of water sensitivity therapeutic agent as delivery vehicle only to obtain limited success.For example; Burghart (US6,306,843) mentioned some prior art stable in medicinal non-aqueous organic solvent for example; acetylsalicylic acid solution in propylene glycol, ethanol, glycerol or the Polyethylene Glycol prepares them to attempt avoiding the hydrolysis of water sensitivity chemical compound.He reports title, even in these solvents, can not eliminate fully vestige moisture and follow take off esterification.
Hollenbeck (US2006/0134148) discloses the aqueous suspension of some drugs delivery system, and it comprises the pearl that contains water soluble drug, and described medicine can be controlled the material coating of highly soluble drug release and be immersed in the aqueous dispersion media.In addition, it is reported, use the product of Hollenbeck drug delivery system to have the long shelf life, because described medicine keeps being limited in the decentralized photo and any functional coating is kept perfectly.These compositionss it is said and comprise:
(a) decentralized photo, it comprises the solvable low-molecular-weight excipient of ion exchange matrix medicinal composition and non-electrolysis, the water solublity electrolyte medicine that described complex comprises medicinal ion exchange matrix and associates with described ion exchange matrix, the surface charge of wherein said ion exchange matrix is opposite with the surface charge of electrolyte medicine; With
(b) disperse medium.
Livney (2011/0038942) discloses some colloid-stabilised nanoparticle dispersion that comprises beta lactoglobulin and polysaccharide, and described nano-particle is transparent when dilution in water-bearing media and reports that it especially can be used as the delivery vector of hydrophobic dietetic product and fatsoluble vitamin.
Lee (US2009/0104251) discloses and has been stated to be heat-staple microcapsule composition, and it can comprise protein, polyanionic polymer and odor mask.Lee further discloses the capsule (encapsulate) that can comprise protein and gelling carbohydrate gum.
Yokoyama, people such as Hideakira (US20050089577) disclose some and it was reported the fluid matrix that claims to experience in vivo phase transfer and liquid oral medicine (that its Chinese medicine can be easy to is dissolved, disperse or suspend and swallow).It is said that described fluid matrix has favourable working properties and high stability owing to its liquid property when sterilization.Yokoyama shows that described substrate also has the effect of sheltering bitterness, and the body inner gelization is with the rate of release of control medicine.
Advantageously, use has the drug delivery system realization of enough stability and/or bioavailability at Jr., old people and/or chronic dose patient's the administration that makes things convenient for, and especially those have the system of savoriness taste for the target group.The gelatin dosage form of prior art can not solve bioavailability and this dual requirements of activating agent stability.
Liquid preparation before for example comprises, the Nano sol preparation may need solvent to increase solution in substrate to make the relatively poor therapeutic agent of dissolubility at first, subsequently only with its evaporation.Perhaps the pH of substrate is adjusted to dissolution treatment agent better.This solubilising of activating agent is disclosed as undesirable, because solubilising may influence the multiple character of activating agent, the cure states of activating agent (namely as described, described activating agent is unbodied still crystal form), it is solid-state etc. that the stability of activating agent in saturation state, how many activating agents are back to.Referring to people such as McGurk, US7,713,551.And the solubilising of activating agent can change pharmacology and the pharmacokinetics feature of activating agent.
Another shortcoming of in these preparation systems some does not keep excessive water (it is essential for effective redispersibility) for them, and therefore the dosage form of the described preparation of any use can show poor drug bioavailability.Except the stability of therapeutic agent in the liquid dispersion system (for example, water sensitivity), they all are important from release performance and their free drug concentration disperse medium of decentralized photo to business success, and they also are the factor of market acceptance level to the palatability of consumer.Therapeutic agent often has the bitterness characteristic, if do not shelter then make them disagreeable to the taste.Described bitterness characteristic also may extend to certain limit other medicines composition component, Food ﹠ Drink composition and filler, further makes the preparation complexity of medicine.Expectation improves the local flavor that comprises the one or more product in these parts, and is especially all the more so in the application that described product is delivered medicine to pediatric patients, and this impels and carries out research work to reduce bitterness for end user's influence.The bitterness characteristic that overcomes medicine is especially problematic in the liquid drug-delivery preparation.For rationally effectively, described odor mask and therapeutic agent preferably should have similar physical property, so that they play similar effect and/or play similar effect (for example about dissolubility or leaching) in the encasing system that designs with receptor.The usual method of realizing the solid oral composition taste masking comprises use flavour enhancer, polymer coating, forms inclusion complex, makes spent ion exchange resin, solubility limits method, liposome, multiple emulsion, use anesthetis etc. with cyclodextrin.Referring to people such as Ettner, " Reducing the Bitterness of Drugs ", Pharmaceutical Formulation﹠amp; Quality, in JIUYUE, 2006.
(Int.J.Pharmaceutics297,38-49 (2005) have reported for the effect of some polyhydric alcohol odor mask to the in-situ gelling pectin preparation that is used for acetaminophen and ambroxol oral and continues to send people such as Miyazaki.It is said and allow assessment bioavailability and therapeutic agent from the lasting release of described gel by the pectin colloidal sol in-situ gelling in rat stomach that contains some therapeutic agent.
The prior art researcher has considered that cyclodextrin is used as the potentiality of bitterness odor mask in oral drugs are sent.(referring to people such as J.Szejtli, Euro.J.Pharmaceutics and Biopharmaceutics, 61,115-125,2005).Except the taste masking ability, researcher reported cyclodextrin can help to improve drug bioavailability by increasing medicine dissolution, increase medicine its absorb site and/or the dissolution rate in preparation and stability and/or reduce drug-induced stimulation (referring to, for example, Pandya, J., " Compatible Polymer used as Characterization Services Size complexes in various drug delivery systems " was committed to Pharminfo.net on March 1st, 2008.
Usually cyclodextrin is incorporated into one of in two ways in the pharmaceutical composition with the auxiliary bitterness of sheltering.That uses therapeutic agent in some cases in compositions is prefabricated into complex or clathrate compound.Yet the latent defect that Friesen has described described method is for the medicine that is prefabricated into: cyclodextrin complexes mix needs in the dosage form preparation,, separation and the described complex of purification.(referring to people such as Friesen, the open text 2008/0075784 of United States Patent (USP)).Perhaps, some therapeutic agents can be with the cyclodextrin dry blend and with physical mixture but not be prefabricated into composite form and be added in the described pharmaceutical composition.Described method also can have shortcoming.Do not provide enough taste maskings for it is to confirm this viewpoint, to have the medicine of the unhappy sense of taste and some physical mixtures of cyclodextrin (for example, dry blend).For example, the simple mixtures of cetirizine and beta-schardinger dextrin-it is reported the bitterness (almost feeling immediately) that still has cetirizine after trial test.(United States Patent (USP) referring to people such as Friesen discloses 2008/0075784).
Perhaps, Fanarra, US2002/0032217A1 discloses prefabricated (rather than with cyclodextrin and cetirizine blend) medicine: cyclodextrin complexes, and subsequently the complex that is prefabricated into is incorporated in the dosage form.Fanarra discloses owing to prefabricated medicine: cyclodextrin complexes forms cetirizine that bitterness reduces and the solution of beta-schardinger dextrin-.
Although cyclodextrin uses in medicinal application, Hladon has reported, than non-compound therapeutic agent, the stability of ibuprofen/beta-schardinger dextrin-complex increases (referring to people such as Hladon (J.Inclusion Phenomena and Macrocyclic Chemistry36 in time in the temperature that raises, 1-8,2000)).Other report has chemical compound lot, wherein cyclodextrin compound have make them be unsuitable for the shortcoming of medicinal usage.Referring to J.Szejtli, Pharmaceutical Technology, 1991,2438; With United States Patent (USP) 5,362,860.Therefore, should consider useful and/or detrimental effect about multiple character.For example; Tee and Takasaki (Can.J.Chem.63; 3540-35441985) investigated the stability of water sensitivity therapeutic agent aspirin and cyclodextrin compound tense; and draw to draw a conclusion: although the dissolubility of aspirin in aqueous solution can by use α-and the beta-schardinger dextrin-complexing agent strengthen, " their trials of being used for medicament purpose of any use should consider that all cyclodextrin promotes the deacetylated ability of aspirin at aqueous solution." (referring to the 3540th page of Tee and Takasaki).Therefore, in some cases, although one or more character such as bioavailability can be improved by independent use cyclodextrin complexes, the potential that other side such as storage stability, effectiveness and/or side effect increase may be because using these identical cyclodextrin to affect adversely immodestly.
Advantageously make water provide the water stability pharmaceutical composition to the minimized therapeutic agent of the influence of therapeutic agent or its model of action and by its liquid dosage form of deriving.For the water sensitivity therapeutic agent especially like this, water sensitivity therapeutic agent hydrolysis (particularly in storage process, and particularly in the aqueous drug delivery system) can cause producing by-product, and it reduces total effectiveness and/or the increase side effect.
In addition, needed water stability pharmaceutical composition and the patient not only is easier to oral absorption than tablet by the liquid, aqueous dosage form of its stable storing of deriving, and also be agreeable to the taste concerning the sense of taste.Some place (wherein the quality limitations of water be provided in the ability of the described water sensitivity therapeutic agent in the aqueous solution) in the world, useful making further provides compositions and/or the liquid dosage form of these reagent that can be taken in safely.Therefore, away from place (wherein the quality of water the is not problem) ability for preparing these therapeutic combinations of suitable dose in advance will be conducive to treat the people who infected by some disease, obstacle or disease.Realize that following medicinal suspension liquid dosage form still is challenging, described dosage form comprises active constituents of medicine in decentralized photo, in disperse medium, have low free drug concentration, and after delivering medicine to the patient, can provide from decentralized photo immediately or lasting drug release.Also its for improvement make manufacturer that the medicine that is prefabricated into can be provided: cyclodextrin complexes need not to the dosage form to separate and the described complex of purification.The present invention relates to these and other important goal.
Summary of the invention
Therefore, the present invention partly relates to the water stability pharmaceutical composition, and it is included in the therapeutic agent in the medicinal substrate; With the abnormal flavour screening agent.
In other embodiments, the present invention relates to the liquid form combination of oral medication, it comprises water stability pharmaceutical composition and medicinal aqueous liquid medium, and wherein said water stability pharmaceutical composition is included in therapeutic agent and the abnormal flavour screening agent in the medicinal substrate.
In other embodiments, the present invention relates to prepare the method for water stability pharmaceutical composition, described compositions is included in the therapeutic agent in the preferred gel-type vehicle in the water stability medicinal substrate; With the abnormal flavour screening agent; Described method comprises the preferred gel-type vehicle precursor of therapeutic agent, abnormal flavour screening agent and medicinal substrate precursor is contacted that the time of contact and condition can effectively be provided in the water stability pharmaceutical composition in the preferred gel-type vehicle of medicinal substrate in water-bearing media.
In some embodiments, the present invention relates to test kit, it comprises:
A. the liquid form combination of oral medication in one or more containers; With
B. the description that is used for the described liquid form combination of oral medication of administration; Wherein:
Described liquid form combination of oral medication comprises water stability pharmaceutical composition and medicinal aqueous liquid medium,
Wherein said water stability pharmaceutical composition is included in therapeutic agent and the abnormal flavour screening agent in the medicinal substrate.
In some embodiments, the present invention relates to rehydratable beverage compositions (rehydration beverage composition), it comprises:
The water stability pharmaceutical composition;
Optional mineral or non-mineral nutritional fill-in; With
Medicinal aqueous liquid medium;
Wherein said water stability pharmaceutical composition is included in therapeutic agent and the abnormal flavour screening agent in the water stability medicinal substrate; And
Wherein said aqueous liquid medium comprises isosmotic solution.
In some embodiments, the present invention relates to prevent and/or treat the method for disease, obstacle, disease or their symptom, comprise the liquid form combination of oral medication that comprises water stability pharmaceutical composition and medicinal aqueous liquid medium to patient's administration of needs, wherein said water stability pharmaceutical composition is included in therapeutic agent and the abnormal flavour screening agent in the medicinal substrate.In some preferred embodiments, the present invention partly relates to the in full disclosed this method that prevents and/or treats of this paper, and wherein said acceptable aqueous liquid medium is isotonic liquid and can chooses wantonly and further comprise mineral or non-mineral nutritional fill-in.
In other embodiments, the present invention relates to have the liquid form combination of oral medication of commercial acceptable shelf life, the described shelf life is that those skilled in the art understand.
In certain embodiments, the present invention relates to water stability pharmaceutical composition and liquid form combination of oral medication thereof, the test kit and the rehydratable beverage compositions that comprise described water stability compositions, wherein said compositions and test kit are heat-staple, and therefore can be exposed to, for example, process (retort processing) in about 60 minutes rice steamer formula dry distilling that about 121 ° of C and about 15PSI carry out, or fill pasteurization (hot fill pasteurization) in the heat that about 104 ° of C carry out.
Above and other objects of the present invention, feature and advantage will be easier to understand after considering following detailed Description Of The Invention.
Description of drawings
Fig. 1 shows three kinds of HPLC chromatograms, and it is presented at the stability that 55 ° of C store the ASA in gellan-β CD preparation after 40 days.Initial chromatogram is the analysis of ASA standard substance; The Neutral colour spectrogram has provided the analysis indication of the stability of ASA in gellan of the present invention-β CD " pearl part "; Back one chromatogram is the analysis of the ASA that comprises in the moisture delivery vehicle when stability study finishes.
Fig. 2 shows the figure that the stability of the ASA in gellan of the present invention/β CD preparation is compared with the stability of ASA in the water.
Fig. 3 is the HPLC chromatogram (being equivalent to store for 64 weeks at 20 ° of C) of describing to contain the stability of ASA in the alginate preparation of ASA.
Fig. 4 is presented at the stability of ASA in the gellan-β CD compositions of system of the present invention under the acceleration condition of storage that 55 ° of C store 40 days.
Fig. 5 is presented at the release of ASA from β CD/ gellan pearl compositions of the present invention in the stomach releasing research of simulation.
Fig. 6 a shows and to show after 55 ° of C store 21 days the HPLC chromatogram of ibuprofen stability in gellan-HP β CD preparation.Initial chromatogram is the analysis of the interior mark of ketoprofen and ibuprofen standard substance; The Neutral colour spectrogram has provided the analysis indication of the stability of ibuprofen in gellan of the present invention-HP β CD " pearl part ".
Fig. 6 b is presented at the stability of the ibuprofen in gellan of the present invention-HP β CD compositions of accelerating storage conditions.
Fig. 7 is presented at the stability of the acetaminophen in gellan of the present invention-HP β CD compositions of accelerating storage conditions.
Fig. 8 is presented at the stability of the naproxen sodium in gellan of the present invention-HP β CD compositions of accelerating storage conditions.
Fig. 9 shows three HPLC chromatograms, and it is presented at the unstability that 45 ° of C store the 3 week ASAs of back in distilled water.Initial chromatogram is the analysis of ASA standard substance, and the Neutral colour spectrogram has provided the analysis indication of the stability of ASA in distilled water, and back one chromatogram is the stability analysis of ASA-β CD inclusion complex in distilled water.
The specific embodiment
The detailed description of exemplary
As above use and the present invention in full disclosed, following term unless have describedly in addition, should be understood and has following implication.
As described herein, term " water stability " refers to chemical compound, reagent, substrate, or compositions keeps basically all abilities of necessary treatment, chemistry and/or physical property, described character and described chemical compound in the presence of water, reagent, substrate, or compositions is relevant with water contact character before.About keeping required character, " whole basically " refer to and chemical compound, reagent, substrate, or before the contact of compositions and water relevant those essential attributes at least about 75%, preferred 80%, more preferably 85%, also more preferably 90%, also more preferably 95%, even more preferably 97%, at least about 99%.For example, the water stability pharmaceutical composition refers to following pharmaceutical composition, the integrity of chemistry and/or physical property wherein, and the effectiveness (the especially integrity of the chemistry of therapeutic agent and/or physical property and effectiveness) relevant with the composition of one or more water stability pharmaceutical compositions thus, in compositions and maintenance basically after the aqueous solution that is used for the delivering drugs compositions contact.
As described herein, " pact " is that those skilled in the art understand and to a certain degree change can be arranged under the environment of its use.If the use of described term is considering that those skilled in the art behind the environment of its use also be unclear, then " pact " refers to that described concrete term is to adding 10% or subtract 10%.
As described herein, term " water sensitivity " refers to water and chemical compound, reagent or compositions, or the functional group's physics contact a period of time in chemical compound, reagent or the compositions, and it changes the ability of at least a chemistry or therapeutic properties or function.For example, acetylsalicylic acid (aspirin) is the water sensitivity therapeutic agent, and its acetyl group is easy to last a period of time reaction with water, and the described time is depended on following condition, as the temperature of water and chemical compound (for example, aspirin), reagent or compositions exposure.Last a period of time, aspirin is converted into salicylic acid by contacting with water.The treatment of known acetylsalicylic acid and/or chemical property are different with treatment and/or the chemical property of water-product bigcatkin willow acid and/or acetic acid.Therefore we can say that aspirin is water sensitivity, because its one or more treatments and/or chemical property of contacting the change aspirin of lasting a period of time with water.
As described herein, term " thermally stable compositions " refers to following compositions, wherein said compositions the dry distilling of rice steamer formula or heat fill under the pasteurizing conditions with thermo-contact after, basically all therapeutic agents are retained in the matrix optimization gel-type vehicle of water stability pharmaceutical composition, and wherein the chemistry relevant with the composition of one or more water stability pharmaceutical compositions and/or integrity and the effectiveness (the particularly integrity of the chemistry of therapeutic agent and/or physical property and effectiveness) therefore of physical property obtain reservation basically.It is heat-staple that gellan substrate (gellan matrice) is described as be under UHT and the HTST processing conditions on the net.Referring to Kelcogel Gellan Gum Book, 5
ThEd., in June, 2007 in June.
As described herein, term " commercial acceptable shelf life " refers to that the commodity that comprise compositions of the present invention can keep stable a large amount of degradeds that active therapeutic agent does not take place to reach at least about 6 months down in typical (shelf storage) condition (about 20 ° of C) that stores, preferably at least about 9 months, more preferably at least about 12 months ability.The baking oven storage temperature and the routine that make compositions be exposed to 55 ° of C are usually extracted sample to determine the threshold level of acetylsalicylic acid stability in time.The general discussion of shelf life and correlation analysis method is referring to Medallions Laboratories, Minneapolis, the article of the Mark Sewald of MN and Jon De Vries " Food Product Shelf Life " comprises about shelf-life testing kinetics chapters and sections and Q
10The concept chapters and sections.The use Q of Miao Shuing wherein
10Be that 2 method is for assessment of the storage stability under more typical condition of storage (20 ° of C).
As described herein, term " gel " refers to have the three-dimensional hydrophilic net of chemistry or physical crosslinking, and described net can absorb a large amount of water or aqueous biological fluids.The gel of this paper definition is hydration, therefore contains a certain amount of water that is combined in wherein.The multiple macromolecular limiting examples that can form gel comprises polysaccharide, as for example, alginate, carrageenin, glucosan (destran), gellan, guar gum, hyaluronic acid, amylopectin (pullulan), scleroglucan (schleroglucan), xanthan gum, xyloglucan (xyloglucan), pectin, chitosan etc." gel precursors " or " gellant " typically refers to identical macromole, but do not have water or before hydration.Under the pH of aqueous solution, these gel precursors are preferably formed gel in the presence of water and some ion or a kind of variant.
As described herein, term " gelling of ion specificity " refers to cause by bivalent cation and forms gel and/or any gellant of energy gelation reverse (gellation reversal) in the presence of monovalent cation.Limiting examples comprises alginate/chitosan/pectin and their derivant.
As described herein, term " non--gelling of ion specificity " refers to pass through monovalence or bivalent cation or its combination and causes any gellant that forms gel.Limiting examples comprises gellan and derivant thereof.
As described herein, term " ring-type oligosaccharide " refer to by will be arranged ring formation about 5 to about 10 saccharide residues in conjunction with the chemical compound that forms, the tubular space of wherein sealing allows to accept guest molecule with the formation clathrate compound.
As described herein, term " cyclodextrin " refers to comprise the about 5 cyclic oligomeric glucosides to about 10 glucose residues, and the tubular space of wherein sealing allows to accept guest molecule to form clathrate compound.Representative instance comprise α-, β-and/or gamma-cyclodextrin, or their derivant, or their mixture.
As described herein, term " therapeutic agent: cyclodextrin complexes " refers to that the physics of therapeutic agent and cyclodextrin associates; Preferably, described complex is clathrate compound-type composite form, and wherein said therapeutic agent is arranged in the tubular space that the cyclodextrin main body is sealed as guest molecule.
As described herein, term " at least a portion ", when the linguistic context of the amount that is used in therapeutic agent or abnormal flavour screening agent, refer to independently respectively therapeutic agent and/or abnormal flavour screening agent at least about 5% weight, preferably, about 10%, more preferably from about 15%, also more preferably from about 20%, and therapeutic agent and/or abnormal flavour screening agent gross weight is preferred at least about 25% weight.
As described herein, term " quite most of " refer to the therapeutic agent that in the inventive method and/or compositions, uses at least about 30% compound with cyclodextrin, preferably, about 35%, more preferably from about 40%, and the therapeutic agent gross weight of using is preferred at least about 45% weight.
As described herein, term " whole basically " refers to the compound more than about 50% weight and cyclodextrin of therapeutic agent that the inventive method is used, preferably more than about 60% weight, more preferably more than about 75% weight, even more preferably more than about 90% weight, also more preferably more than about 95% weight, and most preferably compound more than chemical compound and the cyclodextrin of about 99% weight.When the water that comprises in aqueous liquid medium uses, what term " whole basically " referred to the water-bearing media that uses in the methods of the invention is water more than about 50% volume, preferably more than about 60% volume, more preferably more than about 75% volume, even more preferably more than about 90% volume, also more preferably more than about 95% volume, and most preferably water-bearing media be water more than about 99% volume.
As described herein, term " liquid oral dosage form " refers to that wherein therapeutic agent is contained in the dosage form that preferably is suspended in the medicinal water-bearing media.
As described herein, term " water-bearing media " and " aqueous liquid medium " refer to comprise based on the per unit volume liquid medium liquid medium of relative a large amount of water separately.Preferably, described water-bearing media all is water basically, as defined herein.
Therapeutic agent is understood to include native form and the medicinal forms thereof of medicine." medicinal " refers to those chemical compounds, material, compositions, salt and/or dosage form are fit to deliver medicine to the patient in rational medical judgment scope and do not have excessive toxicity, stimulation, anaphylaxis, or other problem or complication, match with rational benefit/risk ratio.Its " medicinal forms " refers to any medicinal derivative or variant, comprises stereoisomer, stereoisomer mixture, enantiomer, solvate, hydrate, isomorphy, polymorph, pseudomorphic crystal, salt form and prodrug.Preferably, in some embodiments, described medicinal forms comprises salt form.Any stereoisomer or the stereoisomer mixture that comprise therapeutic agent at medicinal forms described in other preferred embodiment.
As described herein, term " limited water solubility " refers to be less than about 0.5 gram therapeutic agent/mL water at the dissolution degree of 25 ° of C therapeutic agents, preferably be less than about 0.2g mL water, more preferably less than about 0.1g mL water, also more preferably less than about 0.05g mL water, also more preferably less than about 0.02g mL water, more preferably less than about 0.01g/mL water.
" side effect " refers to use the effect outside the effect that the therapeutic agent expection reaches, and for example, the detrimental effect that medicine produces is especially to except seeking the detrimental effect that the tissue benefited by described administration or the tissue the tract or tract produce.For example, under the situation of aspirin, term " side effect " refers in particular to such as gastric irritation, inflammation, heartburn, feels sick and the such symptom of pain.
" dosage unit " refers to be suitable for the physics discrete unit as dosage unit for concrete individuality to be treated.Constituent parts can comprise the reactive compound of the scheduled volume that produces required therapeutical effect (one or more) as calculated and required pharmaceutical carrier.The specification of dosage unit form of the present invention can be arranged by following factor: (a) specific characteristic of reactive compound and the concrete therapeutical effect (one or more) that will realize and (b) this area intrinsic to mixing the restriction of such reactive compound (one or more).
As described herein, term " preservative system " or " antiseptic " comprise that all approvals are used for the antiseptic of Food ﹠ Drink compositions, comprise, but be not limited to, known chemical preservative such as benzoate (comprise sodium benzoate, calcium benzoate and Potassium Benzoate), sorbate (comprises sodium sorbate, calcium sorbate and potassium sorbate), citrate (comprising sodium citrate and potassium citrate), polyphosphate (comprising sodium hexameta phosphate (SHMP)) and their mixture and antioxidant such as ascorbic acid, EDTA, BHA, BHT, TBHQ, dehydroacetic acid (dehydroacetic acid), dimethyl two carbonate, ethoxy quinoline, P-hydroxybenzoic acid heptyl ester and their combination.Antiseptic can use by the amount of the maximum horizontal that is no more than regulation.
As described herein, term " fruit flavor " refers to those spice derived from phanerogamous edible regenerating section (regenerating section that especially has the hesperidium meat relevant with seed).Term " fruit flavor " also comprises the spice of synthetic preparation, and it simulates the fruit flavor of natural origin through preparation.The limiting examples of fruit flavor comprises that citrus flavors comprises the sub-spice of orange (Fructus Citri tangerinae), lemon flavouring, Citrus aurantium Linn. (lime) spice and grapefruit perfume and such as such spice such as Fructus Mali pumilae, Fructus Vitis viniferae, Fructus Pruni pseudocerasi and Fructus Ananadis comosi spice or their mixture.
As described herein, term " plant perfume " refers to the spice derived from the part outside the fruit of plant.Therefore, plant perfume can comprise derived from the quintessence oil of nut, skin, root and leaf and those spice of extract.Described term " plant perfume " also comprises the spice of synthetic preparation, and it simulates the plant perfume of natural origin through preparation.The example of described spice comprises cola spice, tea flavour etc., and their mixture.
What the invention particularly relates to is wondrous and has unexpectedly invented the new water stability pharmaceutical composition that can deliver medicine to the patient in liquid, aqueous delivery vector.Before the present invention, although use the gel dosage form for a lot of reasons expectation, but between following 2, immanent contradiction is arranged, on the one hand being to wish to have in dosage form more water to increase the redispersion of activating agent, is to know that the water that has high percentage ratio can cause the degraded of the activating agent sent on the other hand.Therefore, in introducing the prior art system of water with the redispersion of promotion medicine, the storage stability of therapeutic agent is had a greatly reduced quality.Find that unexpectedly the existence of water can not make the therapeutic agent instability in the dosage form of the present invention or can not make its degraded.
The advantage that comprises compositions and/or the dosage form of the present composition and/or comprise the test kit of the present composition can include but not limited to: (1) is active agent delivery fast, and it can be relevant with the fast Absorption of therapeutic agent; (2) stability of activating agent, it can comprise the chemical stability of activating agent; (3) activating agent is in redispersibility excellent after the administration or in biological associated media; (4) compare with microgranule or dissolved form with the identical activating agent of same dose administration, described activating agent has bioavailability similar or that improve; (5) compare with microgranule or dissolved form with the identical activating agent of same dose administration, the more consistent bioavailability of activating agent distributes, and helps to determine dosage, and this is because the consistent activating agent particle diameter that exists in the gelatin dosage form; (6) make things convenient for administration, only need to swallow a spot of moisture delivery vehicle that comprises described compositions; (7) sensation of any taste beastly of therapeutic agent obviously reduces; (8) described dosage form is specially adapted to baby, child and gerontal patient crowd, and swallows other patient crowd that pill or other solid dosage forms have difficulties; (9) compare with conventional solid dosage forms such as tablet, owing to being easy to take in and digest has better patient's compliance; That (10) improves protects the water sensitivity therapeutic agent; (11) in moisture delivery vehicle, comprise shelf life of improvement of the dosage form of described compositions.
Therefore, in certain embodiments, the invention provides the water stability pharmaceutical composition, it is included in the medicinal substrate:
Therapeutic agent; With
The abnormal flavour screening agent,
And the method for preparing described water stability pharmaceutical composition.
In some embodiment preferred of the present invention, described water stability pharmaceutical composition 55 ° of C stable reaching at least about 20 days (be equivalent to 20 ° of C about 240 days) basically, uses Q in the presence of aqueous liquid medium
10Be 2 estimations.Preferred described water stability pharmaceutical composition in the presence of aqueous liquid medium 55 ° of C basically stable reaching at least about 25 days (be equivalent to use Q about 300 days of 20 ° of C
10Be 2), more preferably (be equivalent to use Q about 360 days of 20 ° of C at least about 30 days in that 55 ° of C are stable
10Be 2), and more preferably (be equivalent to use Q about 480 days of 20 ° of C at least about 40 days in that 55 ° of C are stable
10Be 2).As described herein, term " stable basically " refers to those embodiments with the launching stability pharmaceutical composition, wherein therapeutic agent keep with water (for example, the water that comprises aqueous liquid medium) relevant whole necessary treatment, chemistry and/or the physical propertys basically of described therapeutic agent before the contact, wherein term " whole basically " as defined herein.
In certain preferred embodiments of the present invention, described water stability pharmaceutical composition provides with liquid oral dosage form, preferably provides with the unit liquid oral dosage form.
In certain preferred aspects, water stability pharmaceutical composition of the present invention, liquid form combination of oral medication, test kit and rehydratable beverage compositions have excellent heat stability (that is, they are heat-staple for common processing conditions).Preferably, when heating in Aquo System, described compositions helps to reduce or prevent matrix break.In other preferred embodiment, have stability and structural intergrity in the rice steamer formula dry distilling processing under about 121 ° of C and about 15PSI of water stability pharmaceutical composition of the present invention, liquid form combination of oral medication, test kit and rehydratable beverage compositions or in the heat filling pasteurization of about 104 ° of C, keep at least about 60 minutes.In other words, when making described water stability pharmaceutical composition be exposed to that the dry distilling of rice steamer formula was processed about 60 minutes or the heat that is exposed to about 104 ° of C when filling pasteurization at about 121 ° of C and about 15PSI, whole therapeutic agents, abnormal flavour screening agent or their complex or combination are retained in the substrate of water stability pharmaceutical composition basically.
Perhaps, the chemistry of any water sensitivity therapeutic agent and/or physical property are not subjected to the influence of Aquo System basically, and described therapeutic agent is placed in the described Aquo System and is exposed to described rice steamer formula dry distilling processing or heat filling pasteurizing conditions.Rice steamer formula dry distilling processing for example is described in, among the 21C.F.R.Section113 (being packaged in the hot worked low sour food in the container that firmly seals).Heat is filled pasteurization and is described among 21C.F.R.Section.114 (acidify food) and the 21C.F.R.Section.131 (milk and butter).According to this mode, described water stability pharmaceutical composition also provides the protection to therapeutic agent such as aspirin, described therapeutic agent in the presence of aqueous liquid medium to the hydrolysis sensitivity.In a more preferred embodiment, described compositions is heat-staple and protection to the water sensitivity therapeutic agent is provided.
In other preferred embodiment, be stable under water stability pharmaceutical composition of the present invention, liquid form combination of oral medication, test kit and the rehydratable beverage compositions processing conditions for UHT (about 1 – of temperature that surpasses about 135 ° of C 2 seconds) or HTST pasteurization (compositions is heated to about 72 ° of C to be kept at least about 15 seconds).
In certain embodiments, water stability pharmaceutical composition of the present invention, liquid form combination of oral medication, test kit and/or beverage composition for treating dental erosion have overcome the shortcoming relevant with prior art by following aspect: having expanded can be by the liquid form combination of oral medication, more preferably liquid, aqueous form combination of oral medication offers the scope of the therapeutic agent of mammalian hosts, thus before comprising because water sensitivity and/or invalid taste masking and those therapeutic agents that can not effectively use.
In some preferred embodiments, water stability pharmaceutical composition of the present invention comprises the beta lactoglobulin that is less than sizable amount, and preferably comprises the beta lactoglobulin of no more than bottom line (de minimis), does not preferably comprise beta lactoglobulin.
In some other preferred embodiment, water stability pharmaceutical composition of the present invention comprises polyoxyethylene-polyoxypropylene triblock copolymer of the general formula E 106P70E106 that is less than sizable amount, the water stability compositions that preferably comprises no more than 15% weight, more preferably no more than 5% weight, polyoxyethylene-polyoxypropylene the triblock copolymer that also more preferably contains the general formula E 106P70E106 of no more than trace, the preferred polyoxyethylene-polyoxypropylene triblock copolymer that does not comprise general formula E 106P70E106.
In other preferred embodiment, the therapeutic agent that comprises in water stability pharmaceutical composition and/or the liquid form combination of oral medication discharges in gastrointestinal tract basically, and more preferably the whole therapeutic agent basically from compositions discharges in gastrointestinal tract.
In certain preferred aspects, the invention provides water stability pharmaceutical composition and/or liquid form combination of oral medication, wherein said substrate comprises gel, more preferably comprises non--ion specificity gel; Also more preferably comprise the non--ion specificity gel that comprises polysaccharide; More preferably comprise the non--ion specificity gel that comprises gellan.
In some preferred embodiment, can be added into compositions with keeping the preferred xanthan gum of chemical compound of gel section shape.Usually, optional with described chemical compound in the process of preparation water stability pharmaceutical composition of the present invention add gel-type vehicle precursor (preferred gellan) before, among or afterwards, but before solidifying, gel is added into compositions, thereby the shape of solidifying the auxiliary described gel-type vehicle in back at gel-type vehicle keeps, and preferred pearl shape keeps.Keep other limiting examples of the chemical compound of gel section shape to comprise locust bean gum and guar gum.
The present invention also part relates to the water stability pharmaceutical composition that comprises the abnormal flavour screening agent, liquid form combination of oral medication, test kit and rehydratable beverage compositions.Can use the abnormal flavour screening agent to reduce the bad taste that the medicinal substrate wherein comprise or one or more therapeutic agents are given.The limiting examples that is used for the abnormal flavour screening agent of medicinal application comprises for example sweetener such as aspartame, sompressible sugar (compressible sugar), dextrates (dextrate), lactose, mannitol, sucrose, maltose, saccharin sodium, Sorbitol and xylitol, nano-lipid granule, ring-type oligosaccharide and spice.Preferably, described abnormal flavour screening agent not with the medicinal substrate chemical bond.
The example that can be used as the spice of abnormal flavour screening agent includes but not limited to food stage spice.Described food stage spice can be synthetic or artificial perfume, natural perfume material or their any mixture.The example of suitable spice includes but not limited to Semen Armeniacae Amarum (almond), almond wine (amaretto), Fructus Mali pumilae (apple), green apple (green apple), Fructus Mali pumilae-Fructus Pruni pseudocerasi-berry (apple-cherry-berry), Fructus Mali pumilae-Mel (apple-honey), Fructus Pruni (apricot), bacon (bacon), fireball (ball of fire), Fructus Musae (banana), barbecue (barbeque), Laurel (bay), beef (beef), roast beef (roast beef), beefsteak (beef steak), berry (berry), blue berry (berry blue), birch beer (birch beer)/PiceameyeriRehd. Et Wils. medicated beer (spruce beer), blackberry (blackberry), Bloody Mary (bloody mary), blue berry (blueberry), the Audun Boysen certain kind of berries (boysenberry), brandy (brandy), bubble gum (bubble gum), butter (butter), butter Semen Juglandis (butter pecan), buttermilk (buttermilk), butterscotch (butterscotch), corn sweety (candy corn), cantaloupe (cantaloupe), cantaloupe Citrus aurantium Linn. (cantaloupe lime), caramel (caramel), Radix Dauci Sativae (carrot), Cortex Cinnamomi (cassia), caviar (caviar), Herba Apii graveolentis (celery), corn (cereal), champagne (champagne), Fructus Pruni pseudocerasi (cherry), Fructus Pruni pseudocerasi cola (cherry cola), cherry wine (cherry maraschino), Fructus seu semen pruni szechuanicae (wild cherry), morello (black cherry), red cherry (red cherry), Fructus Pruni pseudocerasi cola (cherry-cola), Carnis Gallus domesticus (chicken), chocolate (chocolate), chocolate Semen Armeniacae Amarum (chocolate almond), cinnamon flavor (cinnamon spice), mandarin orange (citrus), mandarin orange blend (citrus blend), mandarin orange-Fructus Fragariae Ananssae (citrus-strawberry), Carnis Mactrae (clam), cocoa (cocoa), Cortex cocois radicis (coconut), roasting Cortex cocois radicis (toasted coconut), coffee (coffee), Semen Armeniacae Amarum coffee (coffee almond), laughable (cola), laughable Rhizoma et radix valerianae (cola-vanilla), cookies ﹠ butter (cookies﹠amp; Cream), cold drink (cool), cotton candy (cotton candy), mossberry (cranberry), mossberry-Fructus Rubi (cranberry-raspberry), butter (cream), cream soda (cream soda), Dairy products butter (dairy type cream), Herba Menthae sweet wine (creme de menthe), Fructus Cucumidis sativi (cucumber), black currant (black currant), milk caramel (dulce de leche), eggnog (egg nog), pork fat (pork fat), fats (type fat), Carnis Coilia (anchovy fish), catfish (herring fish), sardine (sardine fish), frankfurter (frankfurter), pungent cuisine (fiery hot), fry Bulbus Allii (fried garlic), fry Bulbus Allii (sauteed garlic), gin (gin), ginger ale (ginger ale), ginger beer (ginger beer), Graham cracker type (graham cracker type), Fructus Vitis viniferae (grape), grapefruit (grape grapefruit), grapefruit-Fructus Citri Limoniae (grapefruit-lemon), grapefruit-Citrus aurantium Linn. (grapefruit-lime), grenadine (grenadine), barbecue (grill), Guarana (guarana), Fructus psidii guajavae immaturus (guava), Semen coryli heterophyllae (hazelnut), Mel (honey), Fructus Capsici (hot), honeydew barbecue (roasted honey), ice cream cone (ice cream cone), Jalapeno (jalapeno), Mexico's Lay lemon (key lime), Fructus actinidiae chinensis (kiwi), Fructus actinidiae chinensis-Fructus Musae (kiwi-banana), Fructus actinidiae chinensis-Fructus Citri Limoniae-Citrus aurantium Linn. (kiwi-lemon-lime), Fructus actinidiae chinensis-Fructus Fragariae Ananssae (kiwi-strawberry), laughable champagne (kola champagne), lard type (lard type), Fructus Citri Limoniae (lemon), Fructus Citri Limoniae ice milk (lemon custard), lemonade (lemonade), pink lemonade (pink lemonade), Fructus Citri Limoniae-Citrus aurantium Linn. (lemon-lime), Citrus aurantium Linn. (lime), Fructus Hordei Germinatus (malt), Fructus Hordei Germinatus milk (malted milk), Fructus Mangifera Indicae (mango), Fructus Mangifera Indicae Fructus Ananadis comosi (mango-pineapple), maple (maple), Margarita (margarita), cotton candy (marshmallow), meat type (meat type), condensed milk (condensed milk), boil milk (cookedmilk), Herba Menthae (mint), seasoning vegetable (mirepoix), mocha (mocha), mochacinna, molasses (molasse), mushroom (mushroom), dip saut (sauteed mushroom), Fructus Melo (muskmelon), Prunus persicanucipersica Schneider (nectarine), neopolitan, verdant (green onion), sauteeing onions (sauteed onion), orange (orange), orange juice (orange cordial), Orange Milkshake (orange creamsicle), fragrant citrus butter (orange creme), Fructus Citri junoris Fructus Persicae Fructus Mangifera Indicae (orange peach mango), Fructus Citri junoris Fructus Fragariae Ananssae Fructus Musae (orange strawberry banana), butter Fructus Citri tangerinae (creamy orange), mandarin orange (mandarin orange), orange-passion-Fructus psidii guajavae immaturus (orange-passion-guava), orange-Fructus Ananadis comosi (orange-pineapple), Fructus Caricae (papaya), passionfruit (passion fruit), Fructus Persicae (peach), Fructus Persicae-Fructus Mangifera Indicae (peach-mango), Semen arachidis hypogaeae (peanut), roasted peanut (roasted peanut), pears (pear), Denmark's type Semen Juglandis (pecan danish type), kernel Semen Caryae Cathayensis (pecan praline), Fructus Piperis (pepper), Herba Menthae (peppermint), allspice (pimento), pina colada (pina colada), pina colada/Fructus Ananadis comosi-Cortex cocois radicis (pina colada/pineapple-coconut), Fructus Ananadis comosi (pineapple), Fructus Ananadis comosi-orange (pineapple-orange), Fructus Pistaciae Verae (pistachio), Pizza (pizza), Punica granatum L. (pomegranate), pork fat type (pork fat type), baked potato (baked potato), dried plum (prune), other strange wine (punch), the other strange wine (citrus punch) of mandarin orange, torrid zone cocktail (tropical punch), the other strange wine (cherry fruit punch) of Fructus Pruni pseudocerasi fruit juice, the other strange wine (grape punch) of Fructus Vitis viniferae, Fructus Rubi (raspberry), black Fructus Rubi (black raspberry), blue Fructus Rubi (blue raspberry), red Fructus Rubi (red raspberry), Fructus Rubi-blackberry (raspberry-blackberry), Fructus Rubi-ginger beer (raspberry-ginger ale), Fructus Rubi-Citrus aurantium Linn. (raspberry-lime), roasting type (roast type), sarsaparilla (root beer), rum (rum), Mulberry lattice Leah light sparkling wine (sangria), sarsa (sarsaparilla), yellow Camphor tree (sassafras), sausage (sausage), sausage Pizza (sausage pizza), savory (savory), seafood (seafood), shrimp (shrimp), walnut cigarette (hickory smoke), mesquite cigarette (mesquite smoke), acid (sour), sour cream (sour cream), sour cream and Bulbus Allii Cepae (sour cream and onion), Herba Menthae Rotundifoliae (spearmint), pungent (spicy), Fructus Fragariae Ananssae (strawberry), Fructus Fragariae Ananssae Margarita (strawberry margarita), jam type Fructus Fragariae Ananssae (jam typestrawberry), Fructus Fragariae Ananssae-Fructus actinidiae chinensis (strawberry-kiwi), caramel (burnt sugar), confection (sweet), super sweet thing (supersweet), sweet acid (sweet﹠amp; Sour), Adeps Bovis seu Bubali (tallow), tamarind (tamarind), red Fructus Citri tangerinae-Citrus aurantium Linn. (tangerine-lime), red Fructus Citri tangerinae (tangerine), tea (tea), mescal type (tequila type), Herba thymi vulgaris (thyme), taffy (toffee), Triple Sec (triple sec), tropical fruit (tree) mixture (tropical fruit mix), turkey (turkey), fruit salad ice cream (tutti frutti), Rhizoma et radix valerianae (vanilla), Rhizoma et radix valerianae butter (vanilla cream), Rhizoma et radix valerianae custard (vanilla custard), french vanilla (french vanilla), vegetable (vegetable), Vermouth (vermouth), vinegar (vinegar), sweetened vinegar (balsamic vinegar), Citrullus vulgaris (watermelon), whiskey (whiskey), the wild certain kind of berries (wildberry), wine (wine), Ilicis Purpureae (winter green) and yoghourt (yogurt).The example of other spice is referring to 21C.F.R. § § 172.510,172.515,172.520,172.530,172.535,172.575,172.580 and 172.585, and it is hereby incorporated by in full.Numerous food level spice is commercially available certainly, for example, and Sensient Flavors Inc., Indianapolis, Ind., Givaudan SA, Cincinnati, Ohio, and International Flavors﹠amp; Fragrances, New York, N.Y.
In other preferred embodiment, the invention provides water stability pharmaceutical composition and/or liquid form combination of oral medication, wherein said abnormal flavour screening agent comprises the ring-type oligosaccharide; More preferably, wherein said ring-type oligosaccharide comprises about 5 to about 10 monosaccharide units; Also more preferably, the mixture of the derivant of the mixture of the wherein said ring-type oligosaccharide derivant that is cyclodextrin or cyclodextrin or cyclodextrin or cyclodextrin; Also more preferably, wherein said cyclodextrin comprise α-, β-or gamma-cyclodextrin, or their derivant or mixture; The cyclodextrin that more preferably comprises alpha-cyclodextrin or beta-schardinger dextrin-, or derivatives thereof or mixture.Also in the preferred embodiment, described ring-type oligosaccharide is the cyclodextrin or derivatives thereof that comprises alpha-cyclodextrin at some.Perhaps, also in the preferred embodiment, described ring-type oligosaccharide is the cyclodextrin or derivatives thereof that comprises beta-schardinger dextrin-at other.
The example that is used for cyclodextrin of the present invention comprise α-, β-, or gamma-cyclodextrin and/or its alkyl and hydroxy alkyl derivant, in certain embodiments, the derivant of beta-schardinger dextrin-and beta-schardinger dextrin-is the most preferred angle of availability cost cost (especially from), or the derivant of alpha-cyclodextrin and alpha-cyclodextrin is most preferred (especially from FDA the viewpoint of the admissible level of consumption of approval) at present in certain embodiments.
That the example of cyclodextrin derivative comprises is single-or many alkylations α-or beta-schardinger dextrin-; Single-or polyhydroxy alkyl α-or beta-schardinger dextrin-; Single-, four-or the seven-α that replaces-or beta-schardinger dextrin-and sulfoalkyl ether cyclodextrin (SAE-CD).The concrete cyclodextrin derivative that can be used for the application comprises HP-, hydroxyethyl-beta-schardinger dextrin-, hydroxypropyl-gamma-cyclodextrin, hydroxyethyl-gamma-cyclodextrin, dihydroxypropyl-beta-schardinger dextrin-, glucosyl group-alpha-cyclodextrin, the glucose group-beta-cyclodextrin, the glucosulfone group-beta-cyclodextrin, malt-base-alpha-cyclodextrin, malt sugar group-beta-cyclodextrin, malt-base-gamma-cyclodextrin, G 3-, maltotriose glycosyl-gamma-cyclodextrin, two malt sugar group-beta-cyclodextrins, methyl-beta-schardinger dextrin-, sulfo group butyl ether cyclodextrin (SBE-CD), and their mixture such as malt sugar group-beta-cyclodextrin, or two malt sugar group-beta-cyclodextrins.In some embodiments, preferred cyclodextrin is beta-schardinger dextrin-.Preferred in other embodiments cyclodextrin is alpha-cyclodextrin.
Generally speaking, ring-type oligosaccharide preferred cyclodextrin plays the effect of host's molecule, and is easy to form inclusion complex (inclusion complex) with multiple guest molecule.For the enclose of success, unique needs are that guest molecule must at least part ofly be engaged in the ring-type oligosaccharide cavity.Each ring-type oligosaccharide has its cavity, thus its size that can hold object wherein especially the number of the monosaccharide by forming ring together limit.Therefore, those skilled in the art can based on the 3D shape of the known inside dimension of contained cavity and required guest molecule select one or more ring-type oligosaccharide as material standed for to form inclusion complex with guest molecule (therapeutic agent that uses as the present invention).
Usually the cavity of ring-type oligosaccharide or bag (pocket) are more hydrophobic than exterior section.Therefore, having more, guest molecule such as the therapeutic agent of hydrophobic property tend to more easily be incorporated in the ring-type oligosaccharide cavity.
The benefit of the compound gained by guest compound and ring-type oligosaccharide preferred cyclodextrin comprises, changes the dissolubility of guest compound; Make it stable, thus the degraded that disadvantageous light action does not take place and/or caused by heat and oxidation; Shelter undesirable physiological action and reduce volatility.Described ring-type oligosaccharide can partly protect drug molecule not attacked by various reactive molecule (being as water in some embodiments of the present invention).
In some embodiment of water stability pharmaceutical composition of the present invention, at least a portion cyclodextrin and at least a portion therapeutic agent are with therapeutic agent: the cyclodextrin complexes form is present in the pharmaceutical composition, more preferably wherein suitable major part and the cyclodextrin of therapeutic agent are compound, and also more preferably wherein all therapeutic agent and cyclodextrin are compound basically.
In some other preferred embodiment, the invention provides water stability pharmaceutical composition and/or liquid form combination of oral medication, wherein said therapeutic agent is selected from the water sensitivity therapeutic agent, more preferably is selected from aspirin, naproxen sodium (naproxen sodium), acetaminophen (acetaminophen) and ibuprofen (ibuprofen).In other preferred embodiment, the invention provides water stability pharmaceutical composition and/or liquid form combination of oral medication, wherein said therapeutic agent is ibandronate (ibandronate sodium).
The present invention partly relates to water stability pharmaceutical composition, liquid form combination of oral medication, test kit and the rehydratable beverage compositions that comprises taste beastly and/or water sensitivity therapeutic agent, and described therapeutic agent can oral administration and have to a certain degree a dissolubility in water.Preferably, described therapeutic agent has limited water solubility.The present invention has taste beastly and/or makes us the application expected especially for having in the water-sensitive pharmaceutical composition at therapeutic agent.The present invention also therein medicine only slowly be dissolved in the water and/or have under the certain situation of low taste threshold value (taste threshold) (that is, can detect the described medicine of low dissolved substance concentration by the taste of medicine) and have purposes.Perhaps, those therapeutic agents that occur in the product of preferably in the shop, selling.Perhaps, any therapeutic agent that preferably in pill, tablet or capsule form or the numerous OTC medicines based on the syrup form of alcohol, uses at present.The indication relevant with the therapeutic agent of selling in these shops includes but not limited to the indication relevant with following medicine: any cough, flu and/or influenza medicine; Medicine, antihistamine drug and/or the anaphylaxis medicine, specially good effect or the general pain therapy medicine that are used for the hole of any kind; Department of pediatrics beverage type medicine; Anti-gas (anti-gas) preparation, stomach discomfort (upset stomach) preparation and diarrhoea preparation; Anti-cholesterol preparation, as comprise those preparations of plant sterol and phytobezoar enol (phytostenol) and/or comprise the smoking cessation preparation of nicotine.
Can be used for exemplary treatment agent that can oral administration of the present invention secretes the inhibitor of thing (autocoid) and histamine system in including, but are not limited to and acts on the inorganic and organic compound in following site: peripheral nervous, adrenoreceptor, cholinoceptor, nervous system, skeletal muscle, cardiovascular smooth muscle, blood circulation, synapse site, neural effector tab sites, endocrine and hormone system, immune system, reproductive system, hormonal system, digestion and Excretory system.The therapeutic agent of preferred kind includes, but are not limited to antacid, analgesics, anti-anginal drug, antianxiety drugs, anti-arrhythmic, antibacterial, antibiotic, diarrhea medicine, antidepressants, antuepileptic, antifungal agent, antihistaminic, resisting hypertension hypertension agents, anti-inflammatory agent, antiviral agents, cardiac drug, contraceptive, cough medicine, cytotoxin, decongestant, diuretic, be used for the medicine of reproduction-urinary system obstacle, be used for parkinson and relevant disease medicine, be used for rheumatismal medicine, sleeping pill, mineral and vitamin, fat-reducing medicament and gonadal hormone.Veterinary drug also is applicable to the present invention.In certain preferred aspects, described therapeutic agent is not nucleoside or nucleotide.
Instantiation with therapeutic agent of taste beastly comprises acetaminophen, albuterol, aminoguanidine monohydrochloride, aminophylline, amitriptyline, Utimox, the ampicillin, Amlodipine Besylate Tablet, aspirin, azithromycin, barbiturate, berberine hydrochloride, caffeine, calcium carbonate, calcium pantothenate, cephalosporin, cetirizine, chloromycetin, chlordiazepoxide, chloroquine, chlorphenamine, chlorpromazine, cimetidine, ciprofloxacin, clarithromycin, codeine, Pethidine, dextromethorphan, Digitoxin, digoxin, diltiazem hydrochloride, diphenhydramine, phenytoin, Carclura, doxylamine succinate, eletriptan, enoxacin, epinephrine, erythromycin, she replaces forint (ethylefrine hydrochloride) hydrochloric acid, etintidine (etinidine), famotidine, fluconazol, glipizide, guaifenesin (gualfenesin), ibuprofen, the hydrochloric acid indeloxazine, lignocaine, diarsed (Lomotil), loratadine, lupitidine, magnesium oxide, meclizine, methacholine, morphine, naproxen, neostigmine, Ni Fen is for fourth (nifentidine), niperotidine, nizatidine, ofloxacin, acetaminophen, pefloxacin, penicillin, phenobarbital, phenothiazine, Phenylbutazone, phenylpropanolamine, pipemidic acid, pirbuterol hydrochloride, piroxicam, prednisolone, propranolol hydrochloride, pseudoephedrine, the pyridone carboxylic acid antimicrobial drug, ranitidine, roxatidine, salicylic acid, sertraline hydrochloride (sertaraline hydrochloride), 'Xiduofeng ', spironolactone, sulbactam sodium, sulfonamide, the color good fortune is for fixed (sulfotidine), dipyrone, the toluenesulfonic acid sultamicillin, tenidap, terfenadine, theophylline, trimethoprim, tuvatidine, valdecoxib, zaltidine and zonisamide.Another limiting examples is ibandronate.
The therapeutic agent that uses in the method and composition of the present invention can exist by prodrug forms.As described herein, " prodrug " expection comprises any covalently bound carrier, discharges the reactive precursor therapeutic agent that uses in the method and composition of the present invention when described prodrug is delivered medicine to mammalian subject in its body.Term " prodrug " also comprises the therapeutic agent of amount maximum that makes the change active substance of the reaction site that reaches expectation through special design, described prodrug itself is generally non-activity or for required activity minimum activity is arranged, but is converted into bioactive metabolites by biotransformation.Can strengthen the many required quality (for example, dissolubility, bioavailability, preparation etc.) of medicine in view of prodrug is known, therefore if necessary, the therapeutic agent that the present composition and/or method are used can be sent by prodrug forms.Therefore, the present invention includes compositions and the delivering method thereof of prodrug.The prodrug of the therapeutic agent that the present invention uses can prepare in the following manner: the functional group that exists in the modified compound, the modification mode is for making trim to be cracked into parent compound in conventional treatment or the body.
Therefore, prodrug comprises that for example wherein hydroxyl, amino or the carboxyl of this paper are bonded to the therapeutic agent of any group, and when described prodrug was delivered medicine to mammalian subject, described prodrug cracking was to form free hydroxyl group, free amine group or carboxylic acid respectively.Example includes but not limited to acetas, fumarate and the benzoate derivatives of alkohol and amine functional group; With Arrcostab, carbocylic radical ester, aryl ester and alkyl aryl ester, as methyl ester, ethyl ester, propyl diester, isopropyl esters, butyl ester, isobutyl, sec-butyl ester, tertiary butyl ester, cyclopropyl ester, phenylester, benzyl ester and phenethyl ester etc.
In other embodiments, the present invention relates to comprise the liquid form combination of oral medication of water stability pharmaceutical composition and medicinal aqueous liquid medium, described water stability pharmaceutical composition is included in therapeutic agent and the abnormal flavour screening agent in the medicinal substrate; And the method for preparing described liquid form combination of oral medication.In certain preferred aspects, the preferred gel-type vehicle of described medicinal substrate (described substrate comprises therapeutic agent and abnormal flavour screening agent), form discontinuous phase in the liquid form combination of oral medication, wherein said discontinuous phase more preferably provides with the form of gel beads.Although pearl is generally circular or spherical shape, this shape normally is processed into substrate the result of gel.According to the present invention, the shape of gel section and/or size are not crucial, as long as the not obvious interference treatment effect of described gel section or influence the required character of water stability pharmaceutical composition, liquid form combination of oral medication, test kit and rehydratable beverage compositions unfriendly.
In certain preferred aspects, described liquid form combination of oral medication provides with kit form.
In other embodiments, the present invention relates to test kit, it comprises:
A. container, it is equipped with aforesaid liquid form combination of oral medication of the present invention; With
B. the description that is used for the described liquid form combination of oral medication of administration.
In some preferred embodiments, the liquid form combination of oral medication in the kit containers provides individually dosed therapeutic agent.
For the pharmaceutical kit of for example treating pain also within the scope of the invention, described pharmaceutical kit comprises the therapeutic agent that is instructed to be used for the treatment of the treatment of pain effective dose in water stability pharmaceutical composition of the present invention, liquid form combination of oral medication or beverage that is contained in one or more sterile chambers.Can use the well-known conventional sterilizing methods of those skilled in the art that container is sterilized.The sterile chamber of material can comprise independent container on demand, or one or more many parts container, as UNIVIAL
TMTwo parts container (available from Abbott Labs, Chicago, Illinois) institute's example.A plurality of dosage of water stability pharmaceutical composition of the present invention, liquid form combination of oral medication or beverage composition for treating dental erosion can be packaged in the unit dosage forms separately, or are combined into the unitary package form.The description of insert or label form has been indicated and has been treated by the amount of the component of administration, administration instructional criterion and/or be used for the instructional criterion of blending constituent, and it also can be included in the test kit.
In other embodiments, with described water stability pharmaceutical composition and vitamin, mineral, aminoacid, sweetener, spice and/or antiseptic combination with etc. ooze, the form of rehydration or the plain beverage composition for treating dental erosion that supplements the nutrients provides.Ooze in the described grade that comprises water stability pharmaceutical composition of the present invention, in some embodiment preferred of rehydration or the plain beverage composition for treating dental erosion that supplements the nutrients, the preferred gel-type vehicle of the medicinal substrate of described water stability pharmaceutical composition (described substrate comprises therapeutic agent and abnormal flavour screening agent) forms discontinuous phase in the liquid form combination of oral medication, wherein said discontinuous phase more preferably provides with the form of gel beads.Although it is circular or spherical that pearl is generally, this shape is generally the result who substrate is processed into gel.According to the present invention, the shape of gel section and/or size are not crucial, as long as not significantly interference treatment effect or influence the required character of water stability pharmaceutical composition, liquid form combination of oral medication, test kit and rehydratable beverage compositions unfriendly of gel section.
In certain embodiments, with compositions of the present invention as grade known in the art ooze, the part of extra-nutrition element or rehydratable beverage provides, for example, referring to United States Patent (USP) 7,052,725 or 7,160,565, incorporate their disclosed full contents into the application as a reference.
Liquid form combination of oral medication of the present invention and/or beverage composition for treating dental erosion also can comprise other composition as purify waste water, sweetener, food acids, flavoring compositions, preservative system, caffeine, caramel, pigment, dyestuff, defoamer and mineral or non-mineral nutritional fill-in.Be used in sweetener in the beverage and can comprise known natural and artificial sweetener or their mixture that obtain easily arbitrarily that can be used in edible composition or the rehydratable beverage, comprise known can be used in the rehydratable beverage and be the complex carbohydrate of their common concentration.Because the people of many motions does not wish to absorb excessive calorie, therefore employed sugar level is kept lower, be preferably about 2 to 4% of beverage weight.Yet, there is the motion related needs of absorbing the greater amount carbohydrate, especially from the process that prolonged exercise recovers, wherein need carbohydrate (glucose) to replace muscle glycogen.For the diet beverage, any artificial sweetener stable in the beverage purposes can replace common sweetener wholly or in part.The artificial sweetener that can be used for liquid form combination of oral medication of the present invention and/or beverage composition for treating dental erosion also can comprise based on peptide and non-based on the artificial sweetener of peptide and their mixture.Sweetener based on peptide comprises, for example, and aspartame neotame (neotame) and alitame (alitame).Non-sweetener based on peptide comprises, for example, and saccharin sodium, Calcium o-benzolsulfimide, acesulfame-K, Sodium Cyclamate, calcium cyclamater, neohesperidin, dihydrochalcone and sucralose (sucralose).In some applications, as in containing the beverage of caramel, alitame can form precipitate (more not expecting to a certain extent), and it can disturb the overall local flavor impression of end product.In some preferred embodiments, artificial sweetener comprises aspartame.In other preferred embodiment, described sweetener comprises aspartame and acesulfame-K.In other preferred embodiment, described sweetener comprises sucralose.
Liquid form combination of oral medication of the present invention and/or beverage composition for treating dental erosion can comprise one or more flavoring compositions, for example, and fruit flavoured composition, plant flavoring compositions or their mixture.If described flavoring compositions comprises acid, it also was added in the stable solution before adding artificial sweetener.The example that contains the flavoring compositions of acid comprises laughable spice and mandarin orange spice.
The concrete amount that is used for making beverage of the present invention have flavour characteristic flavoring ingredient will depend on selected spice, desired local flavor impression and the form of flavoring ingredient.Those skilled in the art can be identified for realizing the amount of any concrete sapidity ingredient of desired taste impression at an easy rate.
Liquid form combination of oral medication of the present invention and/or beverage composition for treating dental erosion also can comprise common extra composition in the beverage preparation thing (beverage formulation).The limiting examples of described extra composition includes but not limited to, caffeine, caramel, coloring agent or dyestuff, defoamer, colloid, emulsifying agent, solid tea (tea solid), fruit juice, muddy component (cloud component) and mineral and non-mineral nutritional fill-in.
The example of non-mineral nutritional fill-in composition is well known by persons skilled in the art and includes but not limited to, aminoacid, oligopeptide, antioxidant and vitamin comprise vitamin A, D, E (tocopherol), C (ascorbic acid), B1 (thiamine), B2 (riboflavin), B6, B12 and K, nicotinic acid, folic acid, biotin and their combination.The optional common amount of non-mineral nutritional fill-in is general acceptable amount in good production practices, and preferred amount is that about 1% to about 100%RDV(wherein said RDV establishes).When existing, the preferred amount of described non-mineral nutritional fill-in composition is that about 5% to about 20%RDV(wherein said RDV establishes).In particularly preferred embodiments, beverage composition for treating dental erosion of the present invention comprises vitamin E, the optional vitamin C that contains.Suitable aminoacid includes but not limited to, lysine, isoleucine, leucine, threonine, valine, tryptophan, phenylalanine, methionine and L-Selenomethionine.
Ooze in the beverage normally used mineral such as sodium and the potassium except waiting, other suitable mineral includes, but are not limited to calcium, ferrum, zinc, vanadium, selenium, chromium, boron, potassium, manganese, copper and magnesium.
Under the inspiration of the present invention's instruction, other optional conventional liq dosage form and/or beverage ingredient it will be apparent to those skilled in the art that.
In other embodiments, the invention provides the method for preparation the application's water stability pharmaceutical composition of the present invention, comprising:
In water-bearing media, make therapeutic agent and abnormal flavour screening agent and medicinal substrate (preferred gel-type vehicle, more preferably non--ion specificity gel-type vehicle) precursor contact, the time of contact and condition are for effectively providing time and the condition of the medicinal substrate that contains therapeutic agent and abnormal flavour screening agent.Preferably, the substrate that contains therapeutic agent and abnormal flavour screening agent exists with the form of pearl.In other preferred embodiment, by any method known to those skilled in the art described substrate to be separated from water-bearing media, separate or remove, described method is preferably filtration for for example filtration or centrifugal.Described substrate is being separated described substrate, separately or after removing, can chosen wantonly it is washed or otherwise clean to reduce remaining water-bearing media existing and/or it is minimized in stromal surface from water-bearing media.
Therefore, in some other embodiment, the present invention relates to prepare the method for liquid form combination of oral medication, comprising:
Under the time of contact that described liquid form combination of oral medication effectively is provided and condition, make following material contact:
The water stability pharmaceutical composition; With
Medicinal aqueous liquid medium;
Wherein said water stability pharmaceutical composition is included in therapeutic agent and the abnormal flavour screening agent in the medicinal substrate.
In some embodiment preferred of the method for preparing the liquid form combination of oral medication, prepare described water stability pharmaceutical composition by the following method, described method comprises:
The precursor of therapeutic agent abnormal flavour screening agent and medicinal gel-type vehicle is contacted in water-bearing media, and the time of contact and condition effectively provide the water stability pharmaceutical composition.
In some embodiment preferred of the present invention, the complex of therapeutic agent and abnormal flavour screening agent is by what contact described therapeutic agent and described abnormal flavour screening agent to form in water-bearing media, and the time of contact and condition effectively provide described complex.In other preferred embodiment, therapeutic agent is contacted in water-bearing media with the precursor of the complex of abnormal flavour screening agent in water-bearing media with medicinal substrate (more preferably gel-type vehicle), time and the condition of contact effectively form more preferably gel-type vehicle of medicinal substrate, and described substrate is included in therapeutic agent and the abnormal flavour screening agent in the water-bearing media.In some preferred embodiment, with before matrix precursor contacts not the complex to therapeutic agent and abnormal flavour screening agent carry out isolated or purified.
Water stability pharmaceutical composition of the present invention and/or liquid form combination of oral medication can prepare by in the multiple mode well known by persons skilled in the art any.For example, the synthetic described chemical compound of variant of the described method that can understand by following method or by those skilled in the art.All disclosed method related to the present invention expections are carried out with random scale, comprise milligram, gram, number gram, kilogram, thousands of gram or commercial commercial scale.
In the method for preparation water stability pharmaceutical composition of the present invention and/or liquid form combination of oral medication, the interpolation of therapeutic agent, abnormal flavour screening agent and medicinal substrate precursor order is not crucial.Therefore, described therapeutic agent, abnormal flavour screening agent and medicinal substrate precursor can contact with any order in aqueous environment.For the sake of simplicity, they can be added into continuously or simultaneously in the container for the preparation of them.In some preferred embodiments, advantageously be that therapeutic agent is contacted in aqueous environment with the abnormal flavour screening agent, be preferably formed a spot of at least therapeutic agent: abnormal flavour screening agent complex.After contacting with each other, they need not to separate and/or purification therapeutic agent/abnormal flavour screening agent mixture.Described reagent can associate, compound or retaining part is unassociated or unassociated fully.After the merging, the aqueous mixture of therapeutic agent/abnormal flavour screening agent can contact with the medicinal substrate precursor, and the time of contact and condition effectively are provided at the water stability pharmaceutical composition in the medicinal substrate.The gelation that it will be apparent for a person skilled in the art that medicinal gel-type vehicle in water stability Pharmaceutical composition of the present invention obviously took place before described compositions is delivered medicine to the patient, but not took place in vivo after administration composition.
As mentioned above, in some embodiment preferred of water stability pharmaceutical composition and/or liquid form combination of oral medication, described abnormal flavour screening agent comprises the ring-type oligosaccharide.In some preferred embodiments, described ring-type oligosaccharide and therapeutic agent form complex or clathrate compound.Usually these complex can be represented by 1:1 host-guest type complex.For at least a portion of formed complex is provided in the present composition, some general guidances are helpful.Although in compositions of the present invention or prepare the ring-type oligosaccharide: in the method for therapeutic agent complex, ring-type oligosaccharide (or other host's molecule) is not crucial with the mol ratio of therapeutic agent (or guest molecule), but uses the extremely main body of about 1:20 of about 20:1 usually: the object mol ratio.Preferably, about 1:10 is to the ratio of about 10:1, and more preferably from about 1:5 is to about 5:1, in addition more preferably from about 2:1 extremely about 1:2 be used in described compositions and/or its preparation method.Although the ring-type oligosaccharide of 1:1 mol ratio in theory: therapeutic agent should be enough to prepare the whole complex of therapeutic agents basically that comprises in the described preparation solution, preferably adds excessive at least a little host's molecule in some embodiments to increase basically all the object therapeutic agents by compound probability.As described herein, this compound stability, dissolubility and/or the taste masking that will help to improve therapeutic agent.For the purpose of general standard, in mole, the relative therapeutic agent molar excess of ring-type oligosaccharide is about 10%, 20,30,50,75, or even the 100% whole therapeutic agents basically that are enough to usually be compounded in the ring-type oligosaccharide.Can select in the embodiment at some, preferred use about 1.8:1 to the ring-type oligosaccharide of about 1:1.8 mol ratio: therapeutic agent, more preferably from about 1.5:1 is to about 1:1.5. more preferably 1.25:1 about 1:1.25 extremely also, also 1.1:1 about 1:1.1 extremely more preferably from about.
Selectively, in the method for preparation water stability pharmaceutical composition of the present invention, can with described therapeutic agent (preferred water sensitivity and/or bitterness therapeutic agent) and abnormal flavour screening agent (preferred cyclodextrin) before they are incorporated into aqueous environment with any way dry blend known in the art.In some preferred embodiments, described dry blend makes the compound of some degree or association (preferably compound) takes place that this is that those skilled in the art are to understand under instruction of the present invention between therapeutic agent and abnormal flavour screening agent preferred cyclodextrin.
Although do not wish to be fettered by any theory of operation, think that the hydrolysising by-product of drug treatment agent causes side effect to be because undesirable interaction of water sensitivity therapeutic agent and water causes.Therefore, use water stability pharmaceutical composition of the present invention, liquid form combination of oral medication or rehydratable beverage compositions that water in the liquid, aqueous form pharmaceutical composition and the interaction of therapeutic agent are minimized, thereby compare the level that reduction can cause the hydrolysising by-product of side effect with the moisture therapeutic agent delivery system of prior art.Minimize by the interaction that makes water and therapeutic agent, the effect that can improve shelf life and therapeutic agent can be held or compare less that some art methods reduce, thus disease of patient, obstacle, disease or its symptom that prevention or treatment have this to need.
The method that any known can be used for forms liquid form combination of oral medication or beverage composition for treating dental erosion can be used for preparing required compositions.
The concrete amount that is used for making beverage of the present invention have flavour characteristic flavoring ingredient will depend on selected spice (one or more), desired local flavor impression and the form of flavoring ingredient.Those skilled in the art can be identified for realizing the amount of any concrete flavoring ingredient of desired local flavor impression easily.
Liquid form combination of oral medication of the present invention and/or beverage composition for treating dental erosion also can comprise other composition common in the beverage preparation thing.The limiting examples of described other composition comprises, but be not limited to, caffeine, caramel, coloring agent or dyestuff, defoamer, colloid, emulsifying agent, solid tea, fruit juice, muddy composition and mineral and non-mineral matter nutritional supplement comprise dietetic product and dietary supplement.
Exemplary dietetic product and dietary supplement are disclosed in, for example, people such as Roberts, Nutraceuticals:The Complete Encyclopedia of Supplements, Herbs, Vitamins, and Healing Foods (American Nutraceutical Association, 2001) in, it is incorporated herein by reference specially at this.Dietetic product or dietary supplement are also referred to as phytochemical (phytochemical) or functional food, are generally human body is had in medical treatment or a pharmaceutically-active class dietary supplement, vitamin, mineral, medical herbs or the treatment food any.Exemplary dietetic product or dietary supplement include but not limited to phylloxanthin, folic acid, fatty acid (for example DHA and ARA), fruit and plant extract, vitamin and mineral supplement, Phosphatidylserine, thioctic acid, melatonin, glycosamine/chrondroitin, Aloe (Aloe Vera), Guggul (India balsam tree), glutamine, aminoacid (for example, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine), green tea, lycopene, wholefood (whole food), food additive, medical herbs, nutrient for plants, antioxidant, the flavonoid composition of fruit, Radix Oenotherae erythrosepalae oil, Semen Lini, fish oil and marine animal oil and probiotic bacteria.Dietetic product and dietary supplement also comprise through genetically engineered and to be also referred to as " medicinal food (pharmafood) " to have the bioengineered food of required character.The example of non-mineral nutritional fill-in composition is well known by persons skilled in the art and includes but not limited to, aminoacid, oligopeptide, antioxidant and vitamin comprise vitamin A, D, E (tocopherol), C (ascorbic acid), B1 (thiamine), B2 (riboflavin), B6, B12 and K, nicotinic acid, folic acid, biotin and their combination.Optional non-mineral nutritional fill-in exists with general acceptable amount in the good preparation practice usually, and preferably exists with about amount of 1% to about 100%RDV, and wherein said RDV establishes.When existing, the amount that non-mineral nutritional fill-in composition preferably exists is about 5% to about 20%RDV, and wherein said RDV establishes.In an especially preferred embodiment, beverage composition for treating dental erosion of the present invention comprises vitamin E, chooses wantonly to have vitamin C.Suitable aminoacid includes, but not limited to lysine, isoleucine, leucine, threonine, valine, tryptophan, phenylalanine, methionine and L-Selenomethionine.
Ooze mineral common in the beverage such as sodium and the potassium except waiting, other suitable mineral includes but not limited to calcium, ferrum, zinc, vanadium, selenium, chromium, boron, potassium, manganese, copper and magnesium.
Water stability pharmaceutical composition of the present invention, liquid form combination of oral medication and/or beverage composition for treating dental erosion can be used for preventing and/or treating multiple disease, obstacle, disease and or its symptom, for example comprise cough, flu and/or flu-like symptom; Flatulence, stomach discomfort and diarrhoea preparation, nasal sinuses allergy and/or pain.And described compositions also can be used in following one or more situations, and the medicine of administration pill, tablet or capsule form is actually (for example can not swallow the patient of pill) that can not carry out in described situation.Alternative administering mode is even more important for pediatric patients.Therefore, water stability pharmaceutical composition of the present invention, liquid form combination of oral medication and/or beverage composition for treating dental erosion for example can be used in the following beverage, described beverage provides no puzzlement mode for father and mother, thereby will have the drug administration of palatability enhanced form in the child, improve some general healthy aspects (beverage that various health are relevant, comprise and have probiotic bacteria (probiotic), dietetic product, OPC (Oligomeric Proanthocyanidins (Oligomeric Procyanidin)), the active component of herbal remedies etc.), auxiliary health inner cholesterol level and/or the delivering therapeutic agents of reducing resists Medicated cigarette, cigar or tobacco pipe custom as nicotine and/or the auxiliary smoker that can reduce the desire of cigarette.
The chemical compound of this paper can be delivered medicine to mammalian hosts or " patient " by the various ways that is suitable for selected oral administration route, as human host or human patients.
For example, can be with described water stability pharmaceutical composition or liquid form combination of oral medication with the inert diluent oral administration.For oral therapeutic administration, described reactive compound can be combined with excipient and use with forms such as elixir, suspension, syrup.The amount of the active therapeutic agent in the described compositions that therapeutic use arranged is preferably following amount, and it is proper dosage that described amount makes by the dosage of administration, and the dosage (dosage that sales counter is recommended) that more preferably is equal to common recommendation gives.For example, the common sales counter buyer dosage of ibuprofen is every 4-6 hour 200mg.Therefore, in certain embodiments of the invention, proper dosage will comprise or provide 200mg in single dose.Can prepare preferred composition of the present invention or preparation, make oral dosage unit form comprise about 0.1 to about 1000mg active therapeutic agent, and comprise that the scope that is positioned at reactive compound wherein makes up with concrete all that measure and subgroup is closed.
Syrup or elixir can contain any in described water stability pharmaceutical composition and above-mentioned other optional member, comprise, for example as the sucrose of sweeting agent, as methyl parahydroxybenzoate and propyl p-hydroxybenzoate, dyestuff and the spice (as Fructus Pruni pseudocerasi or orange flavor) of antiseptic.Certainly, prepare any material that uses in any dosage unit form be preferably pharmaceutical purity and be to be essentially nontoxic when use amount.In addition, described reactive compound can be incorporated in slow release goods and the preparation.
The dosage that constitutes the therapeutic agent of water stability pharmaceutical composition, liquid form combination of oral medication, test kit and/or beverage composition for treating dental erosion can change according to multiple factor, for example, the pharmacodynamic profile of concrete medicine and administering mode thereof and approach, receiver's age, health and body weight, the nature and extent of symptom, kind, therapeutic frequency and the desired effect of concurrent treatment.Usually, can use low dose at first, and if necessary, increase up to the desired effect that reaches under the described environment with little increment.
What will also be understood that is, be used in therapeutic agent in the treatment or the amount of its active salt or derivant, not only change according to selected concrete medicine or its salt, and change according to the character of route of administration, indication, the symptom for the treatment of and patient's age and situation, and will finally be decided by monitoring doctor or clinicist.
Required dosage can be easily provides with single dose or with the fractionated dose of suitable interval administration, for example, divides two, three, four or more times sub-doses every day.
Described dosage also can discharge to provide by the control of the described chemical compound of the well-known technology of those skilled in the art.
The disclosed content of above-mentioned each piece file is hereby incorporated by with its integral body.
The present invention further describes in following examples.Unless have describedly in addition, described embodiment is actual embodiment.These embodiment only are the illustrative purpose, are not used for limiting appended claim.
The specific embodiment
Experimental section
The described beverage prototype of preparation is used general laboratory glassware and equipment in laboratory scale device.All GRAS chemicals and raw material are available from Audited Suppliers such as Sigma-Aldrich, Fisher Scientific, Acros Organics, CP Kelco and Gold Coast Ingredients.Material: all chemicals are that reagent grade and need not being further purified is used.
Thermally-stabilised testing scheme
Rice steamer formula dry distilling processing
Be test water stability pharmaceutical composition (121 ° of C under rice steamer formula dry distilling condition, at 15PSI) stability in liquid form combination of oral medication or rehydratable beverage compositions are used, the described compositions of 80 grams is added into aluminum rice steamer formula dry distilling jar (211X300mm, Freund Container company, Chicago, Ill.) in and fill the water of 80 ° of C.With described jar use desk-top tin seamer (Dixie Canning Company, Athens, Ga.) sealing, place pilot-scale rice steamer formula retort (Dixie Canning Company, Athens, Ga.) in, and handled 55 minutes at 121 ° of C and 15PSI.Behind the retorting process, open described jar.Remove excessive water and examine under a microscope described pearl.If the gel-type vehicle of described pearl is heat-staple for rice steamer formula dry distilling condition, then described pearl shows as complete.If therapeutic agent is water sensitivity, then the further HPLC that pearl and/or medium are carried out analyzes and can further show heat stability.
Heat is filled processing
For test gel-type vehicle pearl experiences the stability of hot filling condition (104 ° of C are at 15PSI), use MicroThermics pilot-scale heat-processing equipment that liquid form combination of oral medication or rehydratable beverage compositions are carried out hot-working (heat is filled).Described mixture is processed, be configured to 60 seconds at 104 ° of flow velocitys of 500mL/ minute of C use and with retention time.The product temperature of filling the spout place should be about 82 ° of C and catches and is contained in the 250ml medium bottle.After the filling, with described bottle with airtight nut sealing of lid and be inverted 3 minutes so that caps.Then, cool off described bottle in the tank from the beginning by immersing room temperature.After finishing hot filling process, open described bottle.Remove excessive water and examine under a microscope described pearl.If it is heat-staple that the gel-type vehicle of described pearl is filled processing conditions to heat, then described pearl shows as complete.If therapeutic agent is water sensitivity, then the further HPLC that described pearl and/or medium are carried out analyzes and can further show heat stability.
The accelerated stability test operation
Each composition sample is placed the 25mL vial, then be placed in 55 ° of C baking ovens.For the prototype that does not contain pearl (as ' fluid matrix ' type compositions, or fluidized bed type compositions), described vial is filled fully with fluid sample.For those compositionss that contain the gel pearl, the pearl-fluid matrix (they fill described glass container together) of 50/50 (w/v) is arranged.Need about 12.5g pearl/12.5mL liquid medium to fill described bottle.
The HPLC analysis condition that is used for the accelerated stability test operation
ASA HPLC method
The analysis of ASA catabolite uses the Agilent Technologies1200 series HPLC with PDA (photodiode array, detector wavelength 224nm) detector to carry out, in conjunction with Phenominex C18-2 post (25cm x0.39cm internal diameter, 5 μ m particle diameters).Dicyandiamide solution A) H
2O, acetonitrile, phosphoric acid (95.45:4.5:0.05), and B) H
2O, acetonitrile, phosphoric acid (49.95:50:0.05).Solvent B goes through and was increased to 80% from 10% in 20 minutes.Use peak area to confirm stability, described peak area is used for determining that ASA is to salicylic total decomposition percentage ratio.The volume injected of each specimen is 5 microlitres.Relatively the area percentage ratio (RT~17.7-18.2 minute) at ASA peak and the salicylic area percentage ratio of its hydrolyzate (at the peak of RT~19.3-19.4) are to determine hydrolysis degree in time.
Ibuprofen HPLC method
The 1260 type Infinity HPLC systems that Zorbax Eclipse XDB-C84.6x150mm5 μ m post are used for comprising diode array detector, freezing automatic injector, post baking oven, quaternary ammonium solvent pump (quaternary solvent pump) and Chemstation function software (available from Agilent (Richmond VA)).Solvent is for containing the acetonitrile of 0.2% (v/v) triethylamine, and with phosphoric acid with the flow rate regulation of 1.5ml/min to pH3.2.Volume injected is 5 μ l.Use peak area to confirm stability, described peak area is used for determining total decomposition percentage ratio of medicine (ibuprofen).The concordance of the area percentage at given medicine peak is used for definite extent of stability in time.
Acetaminophen and naproxen HPLC method
To use the Agilent Technologies1260 high performance liquid chromatograph that is equipped with photodiode array (PDA) detector to carry out separately at the analysis of acetyl aminophenol and naproxen sodium.The detection wavelength of acetaminophen is that the detection wavelength of 248nm and naproxen sodium is 330nm.HPLC equipment comprises Phenominex C18 (2) post (25cm x0.39cm internal diameter, 5 μ m particle diameters).Dicyandiamide solution is for to last 20 minutes from 90%A to 20%A gradient (water of solvent orange 2 A: 95.45:4.5:0.5, acetonitrile, O-phosphoric acid, the water of solvent B49.95:50:0.05, acetonitrile, O-phosphoric acid).Volume injected is 5 μ l.Stability uses peak area to confirm, described peak area is used for determining total decomposition percentage ratio of medicine (acetaminophen or naproxen).The concordance of the area percentage at given medicine peak is used for definite extent of stability in time.
Sample is at the appointed time taken out and prepares to carry out the HPLC analysis from bottle (the baking oven).For the analysis of the prototype that only contains fluid matrix (that is, not having pearl), maybe when analysis contains the liquid medium of pearl compositions, use following operation to prepare fluid sample and be used for the HPLC analysis.
A part of fluid matrix (1mL) is taken out and is added into the glass centrifuge tube from described bottle.(MeOH 1mL) is added in the centrifuge tube, jolts (vortex) and leaves standstill 1 hour with methanol then.MeOH is used for the auxiliary ASA that removes and/or extract from employed any encapsulation composition (that is, β CD, alginate, gellan or their combination in any).Centrifugal 15 minutes of described sample is settled out any granule with rotation, and shifts out top layer and analyze to be used for further HPLC.
The preparation that is used for the pearl sample of HPLC analysis uses following method to carry out.Pearl material (1 gram) is taken out from bottle and is added in the glass centrifuge tube.(1mL) is added in the centrifuge tube with methanol, and uses little metal spatula grinding to become fines (human eye appears as complete blend) up to pearl in described pipe (having MeOH) on described pearl.Gains were left standstill 1 hour.Sample was settled out granule with rotation in centrifugal 15 minutes, shifts out top layer liquid and be used for further HPLC analysis.
Embodiments of the invention
Embodiment 1
Beta-schardinger dextrin-in the step I. distilled water and ASA complex
The 500mL beaker is placed on the agitator disk (stir-plate).(DH2O) pours in the described beaker with the 87.65mL distilled water.With beta-schardinger dextrin-(β CD, 1.8g) and acetylsalicylic acid (ASA 143mg) is added in the water so that the beta-schardinger dextrin-of about 2:1 mol ratio: ASA to be provided.Mixture was stirred (use stirring rod) about 30 minutes fast.
Step II. preparation contains the gellan microballon of β CD-ASA complex
0.25g sodium citrate (citrate trisodium dihydrate) is dissolved in the aqueous mixture of the β CD-ASA complex that comprises above-mentioned steps I preparation.
With 0.50g KELCOGEL F gellan rubber powder, 0.01g KELTROL T xanthan rubber powder and 4g sugar dry blend together.Be added in the aqueous mixture that contains citrate the gained blend and quick the stirring up to all solids by hydration (that is, not having significant solid).Subsequently 0.10g potassium sorbate and 7.50g sugar are added in the described mixture.With gained mixture continuous stirring up to complete hydration.By being dissolved in, the 10g anhydrous citric acid prepares gel sedimentation bath (gel setting bath) among the 90mL DH2O.The similar operations of preparation gel is referring to Kelcogel Gellan Gum Book, 5
ThEd., June, be hereby incorporated by its integral body in June, 2007.The mixture that will have the complete hydration of viscous liquid outward appearance then is loaded in the 50mL syringe of assembling 20 dividers (gauge) syringe needle, thus the less relatively droplet of preparation.The speed of cementitious mixtures with approximate 1mL/min dropwise is delivered to the sedimentation bath from syringe.In case contact with described sedimentation bath, described drop forms the solid gel pearl immediately.The gel beads that newly forms was placed 1 hour in sedimentation is bathed, separate by bathing from sedimentation to filter the inclusions then, and wash with DH2O.
Step II I. liquid form combination of oral medication
In 100mL DH2O, add 12g sugar, 0.2g citric acid, the natural organic lemon flavouring of 0.4mL, the agent of 0.1g natural cover and 0.1g sodium benzoate and by quick stirring it is dissolved fully, thereby form the fluid matrix part (aqueous liquid medium) of prototype liquid form combination of oral medication.Then gellan glue gel pearl (being derived from above-mentioned part II) is added in the 100mL fluid matrix.Described gellan microballon suspends in resulting composition and spreads all over described fluid matrix.
The acceleration of embodiment 1 stores research
Duplicate sample is stored 40 days at 55 ° of C (be equivalent to store at 20 ° of C 400 days, based on Q
10=2).Between the storage life " the pearl part " and " containing water section " of prototype being carried out HPLC analyzes.Use the methanol of 1:1 ratio (w:v) from described pearl extracting section ASA.After 40 days, the acceleration with gellan-ASA that β CD pearl is prepared is stored the HPLC analysis result (Fig. 1) that carries out show that new preparation provides significant ASA stability (Fig. 2) under these conditions.
The sensory evaluation of embodiment 1
The sensory evaluation that described compositions is carried out shows that the abnormal flavour that does not have ASA-to derive exists.Described method provides the aqueous compositions of high stability ASA solution and does not have obvious abnormal flavour.The sensory testing also shows the abnormal flavour that does not have acetic acid.
0.143g ASA and 1.8g β CD is compound in 100mL DIH2O.2g alginate powder is added in the ASA/ β CD mixture.It is upright to the complete hydration of alginate to stir gains.Then according to above-mentioned at the described identical mode of gellan pearl by described formulations prepared from solutions pearl, described sedimentation that different is is bathed and is calcium chloride solution (100mM), it prepares by 7.35g calcium chloride is added in the 500mL distilled water.Then described pearl is added in the fluid matrix, described fluid matrix be with embodiment 1 in the similar mode of gellan pearl prepare.Carry out the stable storing Journal of Sex Research by the mode identical with gellan (pearl) prototype.
The acceleration of embodiment 2 stores research
Fig. 3 has been provided by the HPLC chromatogram of the pearl of the operation preparation that provides by embodiment 2.Described pearl is stable during accelerating to store research.Figure among Fig. 4 has compared stability and the stability of ASA in water of the ASA for preparing in alginate/β CD pearl compositions.
The sensory evaluation of embodiment 2
Owing to by the inherent abnormal flavour that ASA and other analgesic drug product cause, estimated the organoleptic feature of the compositions of embodiment 2.Find that described preparation has the abnormal flavour that can not identify.
Reduce the gellan pearl of size
Preparation than the pearl of small particle diameter (it approaches the scope that is used in according to estimates in the commercial formulation more closely) to measure and the release dynamics of more less pearl (micron-scale) and the pearl of the 2-3mm size that early prepares.The gellan preparation that uses in this experiment is to prepare by the method similar operation with embodiment 1.
For preparing less pearl, use the air extraction device that gellan is sprayed on the citric acid solution.Design this scheme to approach the commercial formulation that the manufacturing equipment that provides as NISCO has been provided, different is that described NISCO equipment uses pump to send solution to be sprayed, and (venture-effect driven) that the system that we use drives as Venturi effect.
Observe described pearl (preceding-pearl (pre-bead) compositions of the red food dyes of before gelation, mixing) by microscopic method and determine that use has the Nikon Eclipse E400 microscope of coverslip and detects at 400X.Because the non-sphericity matter of granule and the size of variation can not obtain average diameter.
The peptic digestion of external digestion research-simulation
Simulate the test of condition in the stomach with the rate of release of therapeutic agent in the moisture delivery system of assessment the present invention.These conditions are simulated in the following manner.Drip in the solution that comprises pepsin (1mg/ml pepsin) 4N HCl to final pH be 2.0.Pepsin solution (40ml) is added in the 50ml screw lid pipe that 5g α-CD-ASA-gellan or β-CD-ASA-gellan pearl (it is to prepare by the method that is similar to embodiment 1) are housed.Stirring pearl with after being scattered in them in the pepsin solution, the pH of the mixture of sample and pepsin solution is being adjusted to 2.0 to simulate stomach (gastric phase) mutually with 4N HCl.Described mixture was digested 1 hour with 120rpm at 37 ° of C in jolting the device water-bath.At 5,10,40 and 60 minutes, extract the aqueous components sample, with described aqueous specimen at 4 ° of C with 2000xg at centrifugal 10 minutes, and use said method by the HPLC free ASA of clear liquid analytically.
ASA is from the release dynamics (37 ° of C digestion 60 minutes) of gellan-β CD in the outer digestion model system of Fig. 5 display body.The result is presented at 20 fens interior ASA of clock time to be increased from the amount that gellan-β CD pearl preparation discharges.
Embodiment 3 (ibuprofen)
Step I.
Hydroxypropyl in the distilled water (HP β CD) and ibuprofen complex
The 500mL beaker is placed on the agitator disk.(DH2O) pours in the described beaker with the 87.65mL distilled water.With hydroxypropyl (HP β CD, 2.18g) and ibuprofen (163.7mg) be added into water so that the hydroxypropyl of about 2:1 mol ratio to be provided: ibuprofen.Mixture was stirred (use stirring rod) about 30 minutes fast.
Step II.
Preparation comprises the gellan microballon of HP β CD-ibuprofen complex
0.25g sodium citrate (citrate trisodium dihydrate) is dissolved in the aqueous mixture that contains the HP β CD-ibuprofen complex for preparing in above-mentioned steps I.
With 0.50g KELCOGEL F gellan rubber powder, 0.01g KELTROL T xanthan rubber powder and 4g sugar dry blend together.Be added in the aqueous mixture that contains citrate the gained blend and quick the stirring up to all solids all by hydration (that is, not having tangible solid).Then 0.10g potassium sorbate and 7.50g sugar are added in the described mixture.With gained mixture continuous stirring up to complete hydration.By being dissolved in, the 10g anhydrous citric acid prepares gel sedimentation bath among the 90mL DH2O.The similar operations of preparation gel is referring to Kelcogel Gellan Gum Book, 5th Ed., in June, 2007.The mixture that will have the complete hydration of viscous liquid outward appearance subsequently is loaded in the 50mL syringe of assembling 20 divider syringe needles, thus the less relatively droplet of preparation.The speed of cementitious mixtures with approximate 1mL/min dropwise is delivered to the sedimentation bath from syringe.In case contact with described sedimentation bath, described drop forms the solid gel pearl immediately.The gel beads that newly forms was placed 1 hour in sedimentation is bathed, separate by filtering from sedimentation bath inclusions then, and wash with DH2O.
Step II I.
The liquid form combination of oral medication
In 100mL DH2O, add 12g sugar, 0.2g citric acid, the natural organic lemon flavouring of 0.4mL, the agent of 0.1g natural cover and 0.1g sodium benzoate, make it to dissolve fully to form the fluid matrix part (aqueous liquid medium) of prototype liquid form combination of oral medication by quick stirring.Then gellan glue gel pearl (from above-mentioned part II) is added in the described fluid matrix of 100mL.The gellan microballon suspends in resulting composition and spreads all over described fluid matrix.
The acceleration of embodiment 3 stores research
Duplicate sample is stored 21 days (if Q10=2 then is equivalent to store for 36 weeks at 20 ° of C) at 55 ° of C.During shelf life " the pearl part " of prototype being carried out HPLC analyzes.The methanol of ibuprofen with 1:1 ratio (w:v) is extracted from the pearl part.After 21 days, the acceleration with gellan-ibuprofen that HP β CD pearl is prepared is stored the HPLC analysis result that carries out, and (Fig. 6 a) shows that new preparation provides significant ibuprofen stability under these conditions.Not observing ibuprofen in the storage life decomposes.Stability uses peak area to confirm, described peak area is used for determining total decomposition percentage ratio of medicine (ibuprofen).The concordance of the area percentage at given medicine peak is used for definite extent of stability in time.Fig. 6 b shows the uniform stability of ibuprofen in the storage life.
The sensory evaluation of embodiment 3 (ibuprofen)
There is not the abnormal flavour that is derived from ibuprofen in the sensory evaluation demonstration that described compositions is carried out.This method provides the aqueous compositions of the high stability ibuprofen solution of no obvious abnormal flavour.
Embodiment 4 (acetaminophen)
Step I.
Hydroxypropyl in the distilled water (HP β CD) and acetaminophen complex
The 500mL beaker is placed on the agitator disk.(DH2O) pours in the described beaker with the 87.65mL distilled water.With HP-(HP β CD, 2.18g) and acetaminophen (120mg) be added into water so that the hydroxypropyl of about 2:1 mol ratio to be provided: acetaminophen.Mixture was stirred (use stirring rod) about 30 minutes fast.
Step II.
Preparation comprises the gellan microballon of HP β CD-acetaminophen complex
0.25g sodium citrate (citrate trisodium dihydrate) is dissolved in the aqueous mixture of the HP β CD-acetaminophen complex that contains above-mentioned steps I preparation.
With 0.50g KELCOGEL F gellan rubber powder, 0.01g KELTROL T xanthan rubber powder and 4g sugar dry blend together.The gained blend is added in the aqueous mixture that contains citrate and fast and stirs up to all solids all by hydration (that is, not having tangible solid).Subsequently 0.10g potassium sorbate and 7.50g sugar are added in the described mixture.With gained mixture continuous stirring up to complete hydration.By being dissolved in, the 10g anhydrous citric acid prepares gel sedimentation bath among the 90mL DH2O.The similar operations of preparation gel is referring to Kelcogel Gellan Gum Book, 5th Ed., in June, 2007.The mixture that will have the complete hydration of viscous liquid outward appearance then is loaded in the 50mL syringe that assembles 20 divider syringe needles with the less relatively droplet of preparation.The speed of cementitious mixtures with approximate 1mL/min dropwise is delivered to the sedimentation bath from syringe.After described sedimentation bath contacted, described drop formed the solid gel pearl immediately.The gel pearl that newly forms was placed 1 hour in sedimentation is bathed, separated by filtering from sedimentation bath inclusions then, and wash with DH2O.
Step II I.
The liquid form combination of oral medication
Add 12g sugar, 0.2g citric acid, the natural organic lemon flavouring of 0.4mL, the agent of 0.1g natural cover and 0.1g sodium benzoate in the 100mL DH2O and make it to dissolve fully to form the fluid matrix part (aqueous liquid medium) of prototype liquid form combination of oral medication by quick stirring.Then described gellan glue gel pearl (from above-mentioned part II) is added in the 100mL fluid matrix.Described gellan microballon suspended in resulting composition spread all over fluid matrix.
The acceleration of embodiment 4 (acetaminophen) stores research
Duplicate sample is stored 21 days (if Q10=2 then is equivalent to store for 36 weeks at 20 ° of C) at 55 ° of C.During shelf life " the pearl part " of prototype being carried out HPLC analyzes.With the methanol of 1:1 ratio (w:v) from pearl extracting section acetaminophen.After 21 days, the acceleration with gellan-acetaminophen that HP β CD pearl is prepared is stored the HPLC analysis result that carries out show that described new preparation provides significant acetaminophen stability (Fig. 7) under these conditions.Between the storage life, do not observe the decomposition of acetaminophen.Use peak area to confirm stability, described peak area is used for determining total decomposition percentage ratio of medicine (acetaminophen).The concordance of the area percentage at given medicine peak is used for definite extent of stability in time.
The sensory evaluation of embodiment 4 (acetaminophen)
There is not the abnormal flavour that is derived from acetaminophen in the sensory evaluation demonstration that described compositions is carried out.This method provides the aqueous compositions of the no obvious abnormal flavour of high stability acetaminophen solution.
Embodiment 5 (naproxen sodium)
Step I.
Hydroxypropyl in the distilled water (HP β CD) and naproxen sodium complex
The 500mL beaker is placed on the agitator disk.(DH2O) pours in the described beaker with the 87.65mL distilled water.With HP-(HP β CD, 2.18g) and naproxen sodium (200.2mg) be added in the water so that the HP-of about 2:1 mol ratio to be provided: naproxen sodium.Mixture was stirred (use stirring rod) about 30 minutes fast.
Step II.
Preparation contains the gellan microballon of HP β CD-naproxen sodium complex
0.25g sodium citrate (citrate trisodium dihydrate) is dissolved in the aqueous mixture of the HP β CD-naproxen sodium complex that contains above-mentioned steps I preparation.
With 0.50g KELCOGEL F gellan rubber powder, 0.01g KELTROL T xanthan rubber powder and 4g sugar dry blend together.Be added in the aqueous mixture that contains citrate the gained blend and quick the stirring up to all solids all by hydration (that is, not having tangible solid).Then 0.10g potassium sorbate and 7.50g sugar are added in the described mixture.With gained mixture continuous stirring up to complete hydration.By being dissolved in, the 10g anhydrous citric acid prepares gel sedimentation bath among the 90mL DH2O.The similar operations of preparation gel is referring to Kelcogel Gellan Gum Book, 5th Ed., in June, 2007.The mixture that will have the complete hydration of viscous liquid outward appearance subsequently is loaded in the 50mL syringe that assembles 20 divider syringe needles to prepare less droplet.The speed of described cementitious mixtures with approximate 1mL/min dropwise is delivered to the sedimentation bath from syringe.After described sedimentation bath contacted, described drop formed the solid gel pearl immediately.The gel pearl of this new formation was placed 1 hour in sedimentation is bathed, separated by filtering from sedimentation bath inclusions then, and wash with DH2O.
Step II I.
The liquid form combination of oral medication
Add 12g sugar, 0.2g citric acid, the natural organic lemon flavouring of 0.4mL, the agent of 0.1g natural cover and 0.1g sodium benzoate in the 100mL DH2O and make it to dissolve fully to form the fluid matrix part (aqueous liquid medium) of prototype liquid form combination of oral medication by quick stirring.Then gellan glue gel pearl (from above-mentioned part II) is added in the described fluid matrix of 100mL.Described gellan microballon is suspended in resulting composition spread all over described fluid matrix.
The acceleration of embodiment 5 (naproxen sodium) stores research
Duplicate sample is stored 21 days at 55 ° of C (if Q10=2 then be equivalent to store for 36 weeks at 20 ° of C).During shelf life " the pearl part " of prototype being carried out HPLC analyzes.Use the methanol of 1:1 ratio (w:v) from the pearl part, to extract naproxen sodium.After 21 days, the HPLC analysis result that the acceleration with gellan-naproxen sodium that HP β CD pearl is prepared is stored shows that new under these conditions preparation provides significant naproxen sodium stability (Fig. 8).Not observing acetaminophen in the storage life decomposes.Use peak area to confirm stability, described peak area is used for determining total decomposition percentage ratio of medicine (naproxen sodium).The concordance of the area percentage at given medicine peak is used for definite extent of stability in time.
The sensory evaluation of embodiment 5 (naproxen sodium)
The sensory evaluation that described compositions is carried out shows the abnormal flavour that does not have naproxen sodium-derive.This method provides the aqueous compositions of the high stability naproxen sodium solution of no obvious abnormal flavour.
The comparative example
Accelerate to store research with detect ASA in distilled water, the stability of ASA in acidify (1% citric acid) distilled water and the stability of the molecule inclusion complex (in distilled water) of ASA-β CD.Each duplicate sample of Processing of Preparation, described sample contains 143mg ASA/8oz distilled water.For the processing that comprises ASA-β CD complex, described in the part I of above prototype formulations operation, use the β CD:ASA of 2:1 ratio.Described processing was stored for 3 weeks to measure ASA to the salicylic hydrolysis rate of its catabolite at 45 ° of C.Use the Agilent Technologies1200 series HPLC with PDA (photodiode array) detector to carry out to the analysis of catabolite, in conjunction with Phenominex C18-2 post (25cm x0.39cm internal diameter, 5 μ m particle diameters).Dicyandiamide solution A) H
2O, acetonitrile, phosphoric acid (95.45:4.5:0.05), and B) H
2O, acetonitrile, phosphoric acid (49.95:50:0.05).Solvent B goes through and rose to 80% from 10% in 20 minutes.Stability uses peak area to confirm, described peak area is used for determining that ASA is to salicylic total decomposition percentage ratio.Fig. 9 be presented in the distilled water ASA to salicylic acid near quantitative decomposition with accelerating to store in the research in distilled water ASA by beta-schardinger dextrin-molecule encapsulation.Obtained similar results for the water with the citric acid acidify.Estimated the organoleptic attribute of β CD-ASA solution.Find that described complex does not make us uncomfortable taste.
Comparative Examples (ASA-gellan preparation, w/o cyclodextrin)
Step I.
ASA is in distilled water
The 500mL beaker places on the agitator disk.(DH2O) pours in the described beaker with the 87.65mL distilled water.(ASA 143mg) is added in the described water with acetylsalicylic acid.Mixture is stirred (use stirring rod) fast to be dissolved fully up to ASA.
Step II.
Preparation contains the gellan microballon of ASA
0.25g sodium citrate (citrate trisodium dihydrate) is dissolved in the aqueous mixture of the ASA that contains above-mentioned steps I preparation.
With 0.50g KELCOGEL F gellan rubber powder, 0.01g KELTROL T xanthan rubber powder and 4g sugar dry blend together.Be added in the aqueous mixture that contains citrate the gained blend and quick the stirring up to all solids all by hydration (that is, not having tangible solid to exist).Then 0.10g potassium sorbate and 7.50g sugar are added in the described mixture.With gained mixture continuous stirring up to complete hydration.By being dissolved in, the 10g anhydrous citric acid prepares gel sedimentation bath among the 90mL DH2O.The similar operations of preparation gel is referring to Kelcogel Gellan Gum Book, 5th Ed., in June, 2007.The mixture that will have the complete hydration of viscous liquid outward appearance then is loaded in the 50mL syringe that assembles 20 divider syringe needles to prepare less droplet.The speed of described cementitious mixtures with approximate 1mL/min dropwise is delivered to the sedimentation bath from syringe.Drop and sedimentation form the solid gel pearl after bathing and contacting immediately.The gel beads that newly forms was placed 1 hour in sedimentation is bathed, separate by filtering from sedimentation bath inclusions then, and wash with DH2O.The ASA that the analysis showed that described pearl is carried out has been hydrolyzed to salicylic acid.
Step II I. liquid form combination of oral medication
In 100mL DH2O, add 12g sugar, 0.2g citric acid, the natural organic lemon flavouring of 0.4mL, the agent of 0.1g natural cover and 0.1g sodium benzoate, and make it to dissolve fully to form the fluid matrix part (aqueous liquid medium) of prototype liquid form combination of oral medication by quick stirring.Then gellan glue gel pearl (from above-mentioned part II) is added in the 100mL fluid matrix.Spread all over described fluid matrix in the suspension of the microballon of gellan described in the resulting composition.Described compositions is bitterness.
Embodiment 1: the water stability pharmaceutical composition, it comprises in the medicinal gel-type vehicle of water stability:
Therapeutic agent; With
The abnormal flavour screening agent;
The medicinal gel-type vehicle of wherein said water stability comprises non--ion specificity gel.
Embodiment 2: the water stability pharmaceutical composition of embodiment 1, wherein said therapeutic agent are water-sensitive.
Embodiment 3: embodiment 1 or 2 water stability pharmaceutical composition, wherein said non--ion specificity gel comprises polysaccharide.
Embodiment 4: the water stability pharmaceutical composition of embodiment 3, wherein said polysaccharide comprises gellan.
Embodiment 5: each water stability pharmaceutical composition in the embodiment 1,2,3 and 4, wherein said abnormal flavour screening agent comprises the ring-type oligosaccharide.
Embodiment 6: the water stability pharmaceutical composition of embodiment 5, wherein said ring-type oligosaccharide contain has an appointment 5 to about 10 monosaccharide units.
Embodiment 7: the water stability pharmaceutical composition of embodiment 6, wherein said ring-type oligosaccharide comprises cyclodextrin.
Embodiment 8: the water stability pharmaceutical composition of embodiment 7, wherein said cyclodextrin comprise α-, β-or gamma-cyclodextrin or their derivant or mixture.
Embodiment 9: embodiment 7 or 8 water stability pharmaceutical composition, wherein said cyclodextrin comprises the beta-schardinger dextrin-or derivatives thereof.
Embodiment 10: embodiment 7 or 8 water stability pharmaceutical composition, wherein said cyclodextrin comprises the alpha-cyclodextrin or derivatives thereof.
Embodiment 11: each water stability pharmaceutical composition in the embodiment 1 to 10, wherein said therapeutic agent is selected from aspirin, naproxen sodium, acetaminophen and ibuprofen.
Embodiment 12: each water stability pharmaceutical composition in the embodiment 1 to 10, wherein said therapeutic agent is ibandronate.
Embodiment 13: each water stability pharmaceutical composition in the embodiment 7 to 12, wherein at least a portion cyclodextrin and at least a portion therapeutic agent are with therapeutic agent: the cyclodextrin complexes form is present in the described pharmaceutical composition.
Embodiment 14: each water stability pharmaceutical composition in the embodiment 7 to 13, wherein quite most therapeutic agent and cyclodextrin are compound.
Embodiment 15: each water stability pharmaceutical composition in the embodiment 7 to 14, wherein all therapeutic agent and cyclodextrin are compound basically.
Embodiment 16: each water stability pharmaceutical composition in the embodiment 1 to 9 and 11 and 13 to 15, wherein:
Described therapeutic agent is selected from aspirin, naproxen sodium, acetaminophen and ibuprofen;
Described abnormal flavour screening agent is beta-schardinger dextrin-; With
The medicinal gel-type vehicle of described water stability comprises gellan.
Embodiment 17: each water stability pharmaceutical composition in the embodiment 1 to 8,10,11 and 13 to 15, wherein:
Described therapeutic agent is selected from aspirin, naproxen sodium, acetaminophen and ibuprofen;
Described abnormal flavour screening agent is alpha-cyclodextrin; With
The medicinal gel-type vehicle of described water stability comprises gellan.
Embodiment 18: each water stability pharmaceutical composition in the embodiment 1 to 9,11 and 13 to 15, wherein:
Described therapeutic agent is selected from aspirin, naproxen sodium, acetaminophen and ibuprofen;
Described abnormal flavour screening agent is hydroxypropyl; With
The medicinal gel-type vehicle of described water stability comprises gellan.
Embodiment 19: each water stability pharmaceutical composition in the embodiment 1 to 11 and 13 to 18, wherein said therapeutic agent is aspirin.
Embodiment 20: each water stability pharmaceutical composition in the embodiment 1 to 11 and 13 to 18, wherein said therapeutic agent is naproxen sodium.
Embodiment 21: each water stability pharmaceutical composition in the embodiment 1 to 11 and 13 to 18, wherein said therapeutic agent is acetaminophen.
Embodiment 22: each water stability pharmaceutical composition in the embodiment 1 to 11 and 13 to 18, wherein said therapeutic agent is ibuprofen.
Embodiment 23: each water stability pharmaceutical composition in the embodiment 1 to 9 and 12 to 15, wherein:
Described therapeutic agent is ibandronate;
Described abnormal flavour screening agent is beta-schardinger dextrin-; With
The medicinal gel-type vehicle of described water stability comprises gellan.
Embodiment 24: each water stability pharmaceutical composition in the embodiment 1 to 8,10 and 12 to 15, wherein:
Described therapeutic agent is ibandronate;
Described abnormal flavour screening agent is alpha-cyclodextrin; With
The medicinal gel-type vehicle of described water stability comprises gellan.
Embodiment 25: each water stability pharmaceutical composition in the embodiment 1 to 9 and 12 to 15, wherein:
Described therapeutic agent is ibandronate;
Described abnormal flavour screening agent is hydroxypropyl; With
The medicinal gel-type vehicle of described water stability comprises gellan.
Embodiment 26: each water stability pharmaceutical composition in the embodiment 1 to 25, wherein said gel-type vehicle provides with the form of pearl.
Embodiment 27: each water stability pharmaceutical composition of embodiment 1 to 26, it is liquid oral dosage form.
Embodiment 28: liquid form combination of oral medication; Comprise:
Each water stability pharmaceutical composition in the embodiment 1 to 27; With
Medicinal aqueous liquid medium.
Embodiment 29: the rehydratable beverage compositions comprises:
Each water stability pharmaceutical composition in the embodiment 1 to 27;
Optional mineral or non-mineral nutritional fill-in; With
Medicinal aqueous liquid medium;
Wherein said water-bearing media comprises isosmotic solution.
Embodiment 30: test kit, it comprises:
A. the liquid form combination of oral medication of the embodiment in one or more containers 28; With
B. the description that is used for the described liquid form combination of oral medication of administration.
Embodiment 31: prepare the method for water stability pharmaceutical composition, described compositions is included in the medicinal gel-type vehicle of water stability:
Therapeutic agent; With
The abnormal flavour screening agent;
The medicinal gel-type vehicle of wherein said water stability comprises non--ion specificity gel;
Described method comprises following material contacted in water-bearing media, and the time of contact and condition effectively provide in the embodiment 1 to 27 each water stability pharmaceutical composition, and described material is:
Therapeutic agent;
The abnormal flavour screening agent; With
Medicinal gel-type vehicle precursor.
Embodiment 32: the method for the water stability pharmaceutical composition of preparation embodiment 31 wherein at first makes described cyclodextrin contact to form cyclodextrin with therapeutic agent in aqueous solution: the therapeutic agent complex.
Embodiment 33: the method for preparing the water stability pharmaceutical composition of embodiment 31 or 32, the described cyclodextrin in the aqueous solution wherein: the therapeutic agent complex contacts with medicinal gel-type vehicle precursor, to be formed on the medicinal water stability gel-type vehicle of the described complex in the water-bearing media, wherein said precursor comprises gellan.
Embodiment 34: the test kit of embodiment 30, wherein the liquid form combination of oral medication in the kit containers provides the therapeutic agent of individually dosed unit.
Embodiment 35: each water stability pharmaceutical composition of embodiment 1 to 27, wherein processed 60 minutes in the rice steamer formula dry distilling that makes described water stability pharmaceutical composition be exposed to 121 ° of C and 15PSI, or after being exposed to the heat filling pasteurization of 104 ° of C, described therapeutic agent keeps before its rice steamer formula dry distilling or heat is filled the preceding effective force of rendeing a service of institute basically for the treatment of.
Embodiment 36: each water stability pharmaceutical composition in the embodiment 1 to 27, wherein make described water stability pharmaceutical composition temperature exposure after the UHT processing conditions about 1 that surpasses 135 ° of C was to about 2 seconds, or the HTST pasteurizing conditions that is exposed to about 72 ° of C is after at least 15 seconds, described therapeutic agent keep treatment before its UHT processing render a service or HTST processing before all rendeing a service basically of rendeing a service for the treatment of.
When any variable occurs in any composition or any formula more than once, the definition when its definition when at every turn occurring is independent of it other occurs at all.The combination of sub and/or variable allows, as long as this combination obtains stable compositions.
Think that chemical formula used herein, abbreviation and title correctly and have accurately reflected following chemical compound reactant and/or part.Yet character of the present invention and value do not depend on the theoretical correctness (all or part of) of these formulas.Therefore should understand as used herein formula and chemical name and/or abbreviation (belonging to the chemical compound of corresponding indication) and not be used for limiting by any way the present invention, comprise that limiting it is any concrete form or any concrete isomer.
When scope used herein relates to physical property such as molecular weight, or when chemical property such as chemical formula, expection comprises all combinations and sub-portfolio and the specific embodiments wherein of scope.
The content of each patent, patent application and publication that described file is quoted or described is hereby incorporated by with its integral body.
Can lack under the situation that does not have concrete disclosed any element at this paper in this exemplary disclosed the present invention and to implement.Can lack at this paper in this exemplary disclosed the present invention does not have concrete open and does not influence in fact under the situation of any element of basis of the present invention and new feature to implement.
It will be appreciated by those skilled in the art that and to carry out multiple variation and modification to the preferred embodiments of the invention, and can carry out described variation and modification and do not depart from spirit of the present invention.Therefore, the expection claims contain all these equivalent variations in the spirit and scope of the present invention.
Claims (26)
1. water stability pharmaceutical composition, it is included in the medicinal gel-type vehicle of water stability:
Therapeutic agent; With
The abnormal flavour screening agent, described abnormal flavour screening agent comprises the ring-type oligosaccharide;
The medicinal gel-type vehicle of wherein said water stability comprises non--ion specificity gel, described non--ion specificity gel comprises polysaccharide.
2. the water stability pharmaceutical composition of claim 1, wherein said therapeutic agent is water-sensitive.
3. the water stability pharmaceutical composition of claim 1, wherein said polysaccharide comprises gellan.
4. the water stability pharmaceutical composition of claim 3, wherein said ring-type oligosaccharide comprises cyclodextrin.
5. the water stability pharmaceutical composition of claim 4, wherein said cyclodextrin comprise α-, β-or gamma-cyclodextrin or their derivant or mixture.
6. the water stability pharmaceutical composition of claim 5, wherein said cyclodextrin comprises the beta-schardinger dextrin-or derivatives thereof.
7. the water stability pharmaceutical composition of claim 5, wherein said cyclodextrin comprises the alpha-cyclodextrin or derivatives thereof.
8. the water stability pharmaceutical composition of claim 5, wherein said therapeutic agent is selected from aspirin, naproxen sodium, acetaminophen and ibuprofen.
9. the water stability pharmaceutical composition of claim 5, wherein at least a portion cyclodextrin and at least a portion therapeutic agent are with therapeutic agent: the cyclodextrin complexes form is present in the described pharmaceutical composition.
10. the water stability pharmaceutical composition of claim 4, wherein:
Described therapeutic agent is selected from aspirin, naproxen sodium, acetaminophen and ibuprofen;
Described abnormal flavour screening agent is beta-schardinger dextrin-or hydroxypropyl; With
The medicinal gel-type vehicle of described water stability comprises gellan.
11. the water stability pharmaceutical composition of claim 4, wherein:
Described therapeutic agent is selected from aspirin, naproxen sodium, acetaminophen and ibuprofen;
Described abnormal flavour screening agent is alpha-cyclodextrin; With
The medicinal gel-type vehicle of described water stability comprises gellan.
12. the water stability pharmaceutical composition of claim 10, wherein said therapeutic agent are aspirin.
13. the water stability pharmaceutical composition of claim 10, wherein said therapeutic agent are naproxen sodium.
14. the water stability pharmaceutical composition of claim 10, wherein said therapeutic agent are acetaminophen.
15. the water stability pharmaceutical composition of claim 10, wherein said therapeutic agent are ibuprofen.
16. the water stability pharmaceutical composition of claim 10, wherein said gellan substrate provides with the form of pearl.
17. liquid form combination of oral medication; It comprises:
The water stability pharmaceutical composition of claim 1; With
Medicinal aqueous liquid medium.
18. the liquid form combination of oral medication of claim 17, wherein said polysaccharide comprises gellan.
19. the liquid form combination of oral medication of claim 18, wherein said ring-type oligosaccharide comprises cyclodextrin.
20. the liquid form combination of oral medication of claim 19, wherein at least a portion cyclodextrin and at least a portion therapeutic agent are with therapeutic agent: the form of cyclodextrin complexes is present in the described pharmaceutical composition.
21. the method for the water stability pharmaceutical composition of preparation claim 1, described method comprises contacts following material in water-bearing media, and wherein time of contact and condition effectively provide the water stability pharmaceutical composition of claim 1, and described material is:
Described therapeutic agent;
Described abnormal flavour screening agent; With
Medicinal gel-type vehicle precursor.
22. the method for preparing the water stability pharmaceutical composition of claim 21, wherein said therapeutic agent comprises aspirin, naproxen sodium, acetaminophen or ibuprofen.
23. the method for preparing the water stability pharmaceutical composition of claim 21 wherein at first makes described cyclodextrin and described therapeutic agent contact to form cyclodextrin in aqueous solution: the therapeutic agent complex.
24. test kit, it comprises:
A. the liquid form combination of oral medication of the claim 17 in one or more containers; With
B. the description that is used for the described liquid form combination of oral medication of administration.
25. the test kit of claim 24, wherein the liquid form combination of oral medication in described kit containers provides with the form of individually dosed unit therapeutic agent.
26. the rehydratable beverage compositions comprises:
The water stability pharmaceutical composition of claim 1;
Medicinal aqueous liquid medium; With
Optional at least a mineral or non-mineral nutritional fill-in;
Wherein:
Described water-bearing media comprises isosmotic solution.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US38209810P | 2010-09-13 | 2010-09-13 | |
US61/382,098 | 2010-09-13 | ||
US13/231,150 US9018193B2 (en) | 2010-09-13 | 2011-09-13 | Aqueous drug delivery system |
PCT/US2011/051386 WO2012037117A1 (en) | 2010-09-13 | 2011-09-13 | Aqueous drug delivery system comprising off - flavor masking agent |
US13/231,150 | 2011-09-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN103209684A true CN103209684A (en) | 2013-07-17 |
Family
ID=44674918
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2011800546354A Pending CN103209684A (en) | 2010-09-13 | 2011-09-13 | Aqueous drug delivery system comprising off - flavor masking agent |
Country Status (14)
Country | Link |
---|---|
US (4) | US9018193B2 (en) |
EP (2) | EP3210597A1 (en) |
JP (2) | JP5890951B2 (en) |
KR (1) | KR20140007798A (en) |
CN (1) | CN103209684A (en) |
AU (1) | AU2011302293B2 (en) |
BR (1) | BR112013005987A2 (en) |
CA (1) | CA2811202A1 (en) |
IL (1) | IL225149B (en) |
MY (1) | MY162175A (en) |
NZ (1) | NZ608239A (en) |
RU (1) | RU2013116336A (en) |
SG (2) | SG188509A1 (en) |
WO (1) | WO2012037117A1 (en) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015175982A1 (en) * | 2014-05-16 | 2015-11-19 | Vivus, Inc. | Orally administrable formulations for the controlled release of a pharmacologically active agent |
US11623008B2 (en) * | 2014-08-20 | 2023-04-11 | Professional Compounding Centers Of America | Excipient compositions for mucoadhesive pharmaceutical compositions including a synergistic combination of amylopectin, pullulan, hyaluronic acid, and xyloglucan |
CN107406369B (en) | 2014-12-09 | 2021-01-15 | 以西结·戈兰 | Relaxant behavior modulators |
US11528924B2 (en) * | 2014-12-09 | 2022-12-20 | Clearmind Medicine, Inc. | Alcoholic beverage substitutes |
EP3282006B1 (en) * | 2015-04-07 | 2019-07-10 | Nissan Chemical Corporation | Method for preparing liquid medium composition, and preparation device and kit therefor |
US10493083B2 (en) | 2015-10-30 | 2019-12-03 | Cmp Development Llc | Spironolactone aqueous compositions |
WO2018048779A1 (en) * | 2016-09-06 | 2018-03-15 | Children's Medical Center Corporation | Topical trpv1 antagonists and methods and compositions thereof |
CN110167543A (en) * | 2016-09-16 | 2019-08-23 | 锡德克斯药物公司 | Preparation comprising paracetamol and sulfoalkyl ether cyclodextrin |
US20210386732A1 (en) * | 2018-01-15 | 2021-12-16 | Seattle Gummy Company | Semi-solid anti-histamine compositions and methods of making and using thereof |
US10828286B2 (en) * | 2018-05-24 | 2020-11-10 | Gm Pharmaceuticals, Inc. | Niacin and berberine compositions and methods of use thereof |
US20210253746A1 (en) * | 2018-06-29 | 2021-08-19 | Roquette Freres | Novel hydroxypropyl-beta-cyclodextrin and process for the production thereof |
JP2020019731A (en) * | 2018-07-31 | 2020-02-06 | 日本食品化工株式会社 | Bitter taste inhibitor of amlodipine besilate |
JP6711875B2 (en) * | 2018-08-29 | 2020-06-17 | 日本食品化工株式会社 | Bitterness suppressant for macrolide compounds |
US11452690B1 (en) * | 2021-01-27 | 2022-09-27 | ECI Pharmaceuticals, LLC | Oral liquid compositions comprising amlodipine besylate and methods of using the same |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040019012A1 (en) * | 2002-02-22 | 2004-01-29 | Singh Satish K. | Ophthalmic antibiotic drug formulations containing a cyclodextrin compound and cetyl pyridinium chloride |
US20090155409A1 (en) * | 2007-12-17 | 2009-06-18 | Sexton Frederick A | Sustained release of nutrients in vivo |
US20090215735A1 (en) * | 2002-02-25 | 2009-08-27 | Alcon, Inc. | Topical solution formulations containing a corticosteroid and a cyclodextrin |
Family Cites Families (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2588189B1 (en) | 1985-10-03 | 1988-12-02 | Merck Sharp & Dohme | LIQUID-GEL PHASE TRANSITION PHARMACEUTICAL COMPOSITION |
FR2647343B1 (en) * | 1989-05-24 | 1994-05-06 | Rhone Poulenc Sante | NOVEL POROUS PHARMACEUTICAL FORM AND ITS PREPARATION |
GB9226391D0 (en) | 1992-12-18 | 1993-02-10 | Cpc International Inc | Xanthan gelling agents |
US5362860A (en) | 1993-02-01 | 1994-11-08 | Warner-Lambert Company | Neutral stabilization complex for CI-979 HCl, a cognition activator |
FR2704146B1 (en) | 1993-04-19 | 1995-07-13 | Cripdom | Microcapsules of acetylsalicylic acid with controlled release. |
US5651980A (en) | 1994-04-15 | 1997-07-29 | Biohybrid Technologies, Inc. | Methods of use of uncoated gel particles |
US6319535B1 (en) | 1995-11-28 | 2001-11-20 | Laurence J. Shaw | Confections that “swim” in a carbonated beverage |
JP3881699B2 (en) | 1996-10-09 | 2007-02-14 | ジボーダン―ルール(アンテルナシヨナル)ソシエテ アノニム | Method for producing beads as food additive |
WO1998023292A1 (en) | 1996-11-29 | 1998-06-04 | Monsanto Company | Lubricious self-standing (intact) gel for oral delivery of biologically-active ingredients |
US5776431A (en) | 1997-03-26 | 1998-07-07 | Galat; Alexander | Water-soluble aspirin composition |
EP0974366B1 (en) | 1997-03-28 | 2006-10-18 | Eisai Co., Ltd. | Oral pharmaceutical preparations decreased in bitterness by masking |
BE1011251A3 (en) | 1997-07-03 | 1999-06-01 | Ucb Sa | Pharmaceutical administrable oral, including an active substance and cyclodextrin. |
AU736539B2 (en) | 1997-07-15 | 2001-08-02 | Kurt Burghart | Method for producing stable acetylsalicylic acid solutions |
JP2004500305A (en) | 1997-10-31 | 2004-01-08 | フアルマシア・コーポレーシヨン | Sustained-release composition containing gellan gum gel |
US6572898B2 (en) | 1999-05-21 | 2003-06-03 | Pts Labs Llc | Electrolyte gels for maintaining hydration and rehydration |
SK282717B6 (en) | 2000-03-10 | 2002-11-06 | �Stav Experiment�Lnej Farmakol�Gie Sav | Preparation method of ultrahigh molecular hyaluronans |
EP1328165B1 (en) | 2000-10-16 | 2007-10-10 | PepsiCo, Inc. | Method for preparing calcium-supplemented beverages |
US7141555B2 (en) | 2000-12-19 | 2006-11-28 | Cephalon, Inc. | Modafinil compound and cyclodextrin mixtures |
US7494669B2 (en) | 2001-02-28 | 2009-02-24 | Carrington Laboratories, Inc. | Delivery of physiological agents with in-situ gels comprising anionic polysaccharides |
WO2003074086A1 (en) | 2002-03-04 | 2003-09-12 | Medrx Co., Ltd. | Liquid matrix undergoing phase transfer in vivo and liquid oral preparations |
AU2003246489A1 (en) | 2002-07-19 | 2004-02-09 | Vitalstate Canada Ltd. | Oral delivery system containing a gel matrix and liposomes |
CA2498207C (en) | 2002-09-11 | 2012-03-13 | Elan Pharma International Ltd. | Gel-stabilized nanoparticulate active agent compositions |
US20060018972A1 (en) | 2002-11-26 | 2006-01-26 | Upm Pharmaceuticals, Inc. | Aqueous sustained-release drug delivery system for highly water-soluble electrolytic drugs |
US7160565B2 (en) | 2003-03-31 | 2007-01-09 | Breakthru Products, Llc | Hydration beverage and method of delivering nutrients |
JP4647493B2 (en) | 2003-09-12 | 2011-03-09 | 株式会社龍角散 | Bitter masking granular jelly beverage |
EP1674088A4 (en) | 2003-10-17 | 2009-04-15 | Medrx Co Ltd | Jelly preparation containing biguanide medicine |
IL160095A0 (en) | 2004-01-28 | 2004-06-20 | Yissum Res Dev Co | Formulations for poorly soluble drugs |
WO2006004574A2 (en) * | 2004-02-19 | 2006-01-12 | Abbott Laboratories | Method for using gamma cyclodextrin to control blood glucose and insulin secretion |
EP1758557B1 (en) * | 2004-05-11 | 2011-07-13 | Egalet Ltd. | Swellable dosage form comprising gellan gum |
WO2005115341A2 (en) | 2004-05-27 | 2005-12-08 | Advanced Bionutrition Corporation | Microparticles for oral delivery |
EP1771161B1 (en) | 2004-07-22 | 2010-04-21 | Bend Research, Inc | Taste masking formulation comprising the drug in a dissolution-retarded form and/or cyclodextrin in a dissolution-enhanced form |
US20070092561A1 (en) | 2005-06-24 | 2007-04-26 | Don Milne | Water-Soluble Aspirin Composition |
US8715731B2 (en) | 2006-03-22 | 2014-05-06 | Isp Investments Inc. | Process of reducing the bitter taste of water soluble actives by co-grinding the active with β cyclodextrin |
PT103476B (en) | 2006-05-10 | 2008-09-19 | Univ De Coimbra | PRODUCTION AND INSULATION PROCESS OF POLYMERIC MICRO- AND NANOPARTICLES CONTAINING MACROMOLECULES OF HYDROFYLIC AND THERMOLIBLE NATURE |
US7988992B2 (en) | 2006-07-06 | 2011-08-02 | KOS Life Sciences Abbott Laboratories | Superporous hydrogels for heavy-duty applications |
US20100015227A1 (en) | 2006-07-14 | 2010-01-21 | Amos Nussinovitch | Dried electrified hydrocolloid gels having unique structure and porosity |
WO2008012329A2 (en) | 2006-07-28 | 2008-01-31 | V. Mane Fils | Seamless capsules containing high amounts of polyunsaturated fatty acids and a flavouring component |
GB0616794D0 (en) * | 2006-08-24 | 2006-10-04 | Arrow Int Ltd | Solid dosage form |
JP5205909B2 (en) * | 2006-10-18 | 2013-06-05 | 大正製薬株式会社 | Mucosal fluid |
JP5048398B2 (en) * | 2007-06-13 | 2012-10-17 | 大蔵製薬株式会社 | Pharmaceutical composition of antifungal agent |
US8974825B2 (en) | 2007-07-06 | 2015-03-10 | Lupin Limited | Pharmaceutical compositions for gastrointestinal drug delivery |
KR100937625B1 (en) | 2007-08-10 | 2010-01-20 | 주식회사 제닉 | Dissolvable Web Porous Film and Preparing Method Thereof |
US9186640B2 (en) | 2007-08-28 | 2015-11-17 | Pepsico, Inc. | Delivery and controlled release of encapsulated lipophilic nutrients |
WO2009084017A2 (en) * | 2007-10-10 | 2009-07-09 | Rubicon Research Private Limited | Taste-masked orally disintegrating tablets of memantine hydrochloride |
AU2007360026B9 (en) | 2007-10-12 | 2013-07-11 | Ryukakusan Co. Ltd. | Granular jelly beverage for medication and process for producing the same |
US20090104251A1 (en) | 2007-10-22 | 2009-04-23 | Sensient Flavors Inc. | Heat stable microcapsules and methods for making and using the same |
BRPI0822111B8 (en) | 2007-12-20 | 2021-05-25 | Nutricia Nv | liquid makeup, and use of a liquid makeup |
CN101938992B (en) | 2008-02-06 | 2013-07-10 | 东英吉利大学 | Composition and method for assisting swallowing |
RU2499592C2 (en) | 2008-04-21 | 2013-11-27 | Отономи, Инк. | Pharmaceutical composition for treating ear diseases |
WO2009130704A1 (en) | 2008-04-24 | 2009-10-29 | Technion Research And Development Foundation Ltd. | Beta-lactoglobulin-polysaccharide nanoparticles for hydrophobic bioactive compounds |
GB0813929D0 (en) | 2008-07-30 | 2008-09-03 | Glaxo Group Ltd | Novel method |
US9414615B2 (en) * | 2010-01-18 | 2016-08-16 | PepciCo, Inc. | Gel-based compositions and methods of making same |
-
2011
- 2011-09-13 RU RU2013116336/15A patent/RU2013116336A/en unknown
- 2011-09-13 JP JP2013528384A patent/JP5890951B2/en not_active Expired - Fee Related
- 2011-09-13 MY MYPI2013700400A patent/MY162175A/en unknown
- 2011-09-13 EP EP16186439.2A patent/EP3210597A1/en not_active Withdrawn
- 2011-09-13 AU AU2011302293A patent/AU2011302293B2/en not_active Ceased
- 2011-09-13 WO PCT/US2011/051386 patent/WO2012037117A1/en active Application Filing
- 2011-09-13 NZ NZ608239A patent/NZ608239A/en not_active IP Right Cessation
- 2011-09-13 KR KR1020137009449A patent/KR20140007798A/en not_active Application Discontinuation
- 2011-09-13 CA CA2811202A patent/CA2811202A1/en not_active Abandoned
- 2011-09-13 CN CN2011800546354A patent/CN103209684A/en active Pending
- 2011-09-13 EP EP11760656.6A patent/EP2616046B1/en active Active
- 2011-09-13 SG SG2013017991A patent/SG188509A1/en unknown
- 2011-09-13 SG SG10201507554RA patent/SG10201507554RA/en unknown
- 2011-09-13 BR BR112013005987A patent/BR112013005987A2/en not_active IP Right Cessation
- 2011-09-13 US US13/231,150 patent/US9018193B2/en active Active
-
2013
- 2013-03-10 IL IL225149A patent/IL225149B/en not_active IP Right Cessation
-
2015
- 2015-03-30 US US14/672,337 patent/US9789191B2/en active Active
-
2016
- 2016-02-19 JP JP2016029886A patent/JP6263699B2/en not_active Expired - Fee Related
-
2017
- 2017-10-17 US US15/786,217 patent/US20180256725A1/en not_active Abandoned
-
2019
- 2019-10-21 US US16/658,524 patent/US20200114011A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040019012A1 (en) * | 2002-02-22 | 2004-01-29 | Singh Satish K. | Ophthalmic antibiotic drug formulations containing a cyclodextrin compound and cetyl pyridinium chloride |
US20090215735A1 (en) * | 2002-02-25 | 2009-08-27 | Alcon, Inc. | Topical solution formulations containing a corticosteroid and a cyclodextrin |
US20090155409A1 (en) * | 2007-12-17 | 2009-06-18 | Sexton Frederick A | Sustained release of nutrients in vivo |
Non-Patent Citations (3)
Title |
---|
DAHNAN D. CHOW ET AL.: "Characterization, dissolution and bioavailability in rats of ibuprofen-β-cyclodextrin complex system", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
OSWALD S.TEE ET AL.: "The cleavage of aspirin by α- and β-cyclodextrins in basic aqueous solution", 《CANADIAN JOURNAL OF CHEMISTRY》 * |
SOMESH CHOUDHURY ET AL.: "Kinetics of aspirin hydrolysis and stabilization in the presence of 2-hydroxypropyl-β-cyclodextrin", 《PHARMACEUTICAL RESEARCH》 * |
Also Published As
Publication number | Publication date |
---|---|
JP5890951B2 (en) | 2016-03-22 |
RU2013116336A (en) | 2014-10-20 |
US20150209435A1 (en) | 2015-07-30 |
EP3210597A1 (en) | 2017-08-30 |
EP2616046A1 (en) | 2013-07-24 |
AU2011302293A1 (en) | 2013-04-04 |
EP2616046B1 (en) | 2016-08-31 |
US20180256725A1 (en) | 2018-09-13 |
MY162175A (en) | 2017-05-31 |
US9018193B2 (en) | 2015-04-28 |
BR112013005987A2 (en) | 2019-09-24 |
US20120122823A1 (en) | 2012-05-17 |
CA2811202A1 (en) | 2012-03-22 |
SG188509A1 (en) | 2013-04-30 |
AU2011302293B2 (en) | 2015-11-26 |
US9789191B2 (en) | 2017-10-17 |
JP2016153401A (en) | 2016-08-25 |
JP2013537891A (en) | 2013-10-07 |
IL225149B (en) | 2018-05-31 |
JP6263699B2 (en) | 2018-01-24 |
SG10201507554RA (en) | 2015-10-29 |
US20200114011A1 (en) | 2020-04-16 |
NZ608239A (en) | 2015-05-29 |
WO2012037117A1 (en) | 2012-03-22 |
KR20140007798A (en) | 2014-01-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103209684A (en) | Aqueous drug delivery system comprising off - flavor masking agent | |
TW544317B (en) | Chewable soft capsules having improved administration properties and process for producing the same | |
CN105248820B (en) | Leaf of Moringa and the composition of brown sugar and its preparation method and application | |
CN104306617B (en) | Composition containing maca and A Sayi fruits and its preparation method and application | |
JPH05186357A (en) | Absorption-inhibitory means for digested product of food/ beverage | |
US10111451B2 (en) | Food, beverage or pharmaceutical composition containing fermented eastern prickly pear and a preparation method therefor | |
CN110366415A (en) | For treating, mitigating and preventing the composition and method of helicobacter pylori infections | |
JP7194375B2 (en) | Coated powdered food and its manufacturing method | |
JP5414995B2 (en) | Acidic urine-improving food and drink and pharmaceutical composition for oral administration comprising fucoidan as an active ingredient | |
CN106470690A (en) | For strengthening compositionss and the method for immunity | |
KR20070012335A (en) | Consumer customized dosage forms | |
JP2011116670A (en) | Method for eliminating malaria, sleeping sickness, aids and hepatitis c and apparatus therefor | |
JP6514240B2 (en) | Composition | |
KR20060128926A (en) | Consumer customized dosage forms | |
JP6849281B2 (en) | Composition containing liver hydrolyzate and Houttuynia cordata extract | |
CN106236697A (en) | Flavoured syrups of discomfort mouthfeel and preparation method thereof when improving oral drug preparation | |
JP6758619B2 (en) | Composition | |
WO2021079961A1 (en) | Food composition | |
JPH03201970A (en) | Ginkgo leaf extract-containing syrup | |
JP2011147392A (en) | Method for eradicating malaria, sleeping sickness, aids and hepatitis c, and device therefor | |
JP2007070266A (en) | Agent for suppressing increase of blood glucose level | |
TW200800152A (en) | Antifatigue composition | |
Singh et al. | THE EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF DIABETES MELLITUS | |
US20130189391A1 (en) | Dry Powdered Comestibles | |
JP2005002089A (en) | Intestinal function improving agent |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20130717 |